Simon E. Fisher

Publications

Displaying 1 - 100 of 200
  • Burenkova, O. V., & Fisher, S. E. (in press). Genetic insights into the neurobiology of speech and language. In E. Grigorenko, Y. Shtyrov, & P. McCardle (Eds.), All About Language: Science, Theory, and Practice. Baltimore, MD: Paul Brookes Publishing, Inc.
  • Fisher, S. E. (in press). Genes and language: Key issues and ways forward. In P. Hagoort (Ed.), Human language: From genes and brain to behavior. Cambridge, MA: MIT Press.
  • Postema, M., Van Rooij, D., Anagnostou, E., Arango, C., Auzias, G., Behrmann, M., Busatto Filho, G., Calderoni, S., Calvo, R., Daly, E., Deruelle, C., Di Martino, A., Dinstein, I., Duran, F. L. S., Durston, S., Ecker, C., Ehrlich, S., Fair, D., Fedor, J., Feng, X., Fitzgerald, J., Floris, D. L., Freitag, C. M., Gallagher, L., Glahn, D. C., Gori, I., Haar, S., Hoekstra, L., Jahanshad, N., Jalbrzikowski, M., Janssen, J., King, J. A., Kong, X., Lazaro, L., Lerch, J. P., Luna, B., Martinho, M. M., McGrath, J., Medland, S. E., Muratori, F., Murphy, C. M., Murphy, D. G. M., O'Hearn, K., Oranje, B., Parellada, M., Puig, O., Retico, A., Rosa, P., Rubia, K., Shook, D., Taylor, M., Tosetti, M., Wallace, G. L., Zhou, F., Thompson, P., Fisher, S. E., Buitelaar, J. K., & Francks, C. (in press). Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets. Nature Communications.
  • Udden, J., Hulten, A., Bendt, K., Mineroff, Z., Kucera, K. S., Vino, A., Fedorenko, E., Hagoort, P., & Fisher, S. E. (in press). Towards robust functional neuroimaging genetics of cognition. The Journal of Neuroscience.
  • Carrion Castillo, A., Van der Haegen, L., Tzourio-Mazoyer, N., Kavaklioglu, T., Badillo, S., Chavent, M., Saracco, J., Brysbaert, M., Fisher, S. E., Mazoyer, B., & Francks, C. (2019). Genome sequencing for rightward hemispheric language dominance. Genes, Brain and Behavior. Advance online publication. doi:10.1111/gbb.12572.

    Abstract

    Most people have left‐hemisphere dominance for various aspects of language processing, but only roughly 1% of the adult population has atypically reversed, rightward hemispheric language dominance (RHLD). The genetic‐developmental program that underlies leftward language laterality is unknown, as are the causes of atypical variation. We performed an exploratory whole‐genome‐sequencing study, with the hypothesis that strongly penetrant, rare genetic mutations might sometimes be involved in RHLD. This was by analogy with situs inversus of the visceral organs (left‐right mirror reversal of the heart, lungs and so on), which is sometimes due to monogenic mutations. The genomes of 33 subjects with RHLD were sequenced and analyzed with reference to large population‐genetic data sets, as well as 34 subjects (14 left‐handed) with typical language laterality. The sample was powered to detect rare, highly penetrant, monogenic effects if they would be present in at least 10 of the 33 RHLD cases and no controls, but no individual genes had mutations in more than five RHLD cases while being un‐mutated in controls. A hypothesis derived from invertebrate mechanisms of left‐right axis formation led to the detection of an increased mutation load, in RHLD subjects, within genes involved with the actin cytoskeleton. The latter finding offers a first, tentative insight into molecular genetic influences on hemispheric language dominance.

    Supplementary material

    gbb12572-sup-0001-AppendixS1.docx
  • Castells-Nobau, A., Eidhof, I., Fenckova, M., Brenman-Suttner, D. B., Scheffer-de Gooyert, J. M., Christine, S., Schellevis, R. L., Van der Laan, K., Quentin, C., Van Ninhuijs, L., Hofmann, F., Ejsmont, R., Fisher, S. E., Kramer, J. M., Sigrist, S. J., Simon, A. F., & Schenck, A. (2019). Conserved regulation of neurodevelopmental processes and behavior by FoxP in Drosophila. PLoS One, 14(2): e211652. doi:10.1371/journal.pone.0211652.

    Abstract

    FOXP proteins form a subfamily of evolutionarily conserved transcription factors involved in the development and functioning of several tissues, including the central nervous system. In humans, mutations in FOXP1 and FOXP2 have been implicated in cognitive deficits including intellectual disability and speech disorders. Drosophila exhibits a single ortholog, called FoxP, but due to a lack of characterized mutants, our understanding of the gene remains poor. Here we show that the dimerization property required for mammalian FOXP function is conserved in Drosophila. In flies, FoxP is enriched in the adult brain, showing strong expression in ~1000 neurons of cholinergic, glutamatergic and GABAergic nature. We generate Drosophila loss-of-function mutants and UAS-FoxP transgenic lines for ectopic expression, and use them to characterize FoxP function in the nervous system. At the cellular level, we demonstrate that Drosophila FoxP is required in larvae for synaptic morphogenesis at axonal terminals of the neuromuscular junction and for dendrite development of dorsal multidendritic sensory neurons. In the developing brain, we find that FoxP plays important roles in α-lobe mushroom body formation. Finally, at a behavioral level, we show that Drosophila FoxP is important for locomotion, habituation learning and social space behavior of adult flies. Our work shows that Drosophila FoxP is important for regulating several neurodevelopmental processes and behaviors that are related to human disease or vertebrate disease model phenotypes. This suggests a high degree of functional conservation with vertebrate FOXP orthologues and established flies as a model system for understanding FOXP related pathologies.
  • Eising, E., Carrion Castillo, A., Vino, A., Strand, E. A., Jakielski, K. J., Scerri, T. S., Hildebrand, M. S., Webster, R., Ma, A., Mazoyer, B., Francks, C., Bahlo, M., Scheffer, I. E., Morgan, A. T., Shriberg, L. D., & Fisher, S. E. (2019). A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Molecular Psychiatry, 24, 1065-1078. doi:10.1038/s41380-018-0020-x.

    Abstract

    Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, we discovered de novo mutations, implicating genes, including CHD3, SETD1A and WDR5. In other probands, we identified novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.

    Supplementary material

    Eising_etal_2018sup.pdf
  • Fisher, S. E. (2019). Human genetics: The evolving story of FOXP2. Current Biology, 29(2), R65-R67. doi:10.1016/j.cub.2018.11.047.

    Abstract

    FOXP2 mutations cause a speech and language disorder, raising interest in potential roles of this gene in human evolution. A new study re-evaluates genomic variation at the human FOXP2 locus but finds no evidence of recent adaptive evolution.
  • French, C. A., Vinueza Veloz, M. F., Zhou, K., Peter, S., Fisher, S. E., Costa, R. M., & De Zeeuw, C. I. (2019). Differential effects of Foxp2 disruption in distinct motor circuits. Molecular Psychiatry, 24, 447-462. doi:10.1038/s41380-018-0199-x.

    Abstract

    Disruptions of the FOXP2 gene cause a speech and language disorder involving difficulties in sequencing orofacial movements. FOXP2 is expressed in cortico-striatal and cortico-cerebellar circuits important for fine motor skills, and affected individuals show abnormalities in these brain regions. We selectively disrupted Foxp2 in the cerebellar Purkinje cells, striatum or cortex of mice and assessed the effects on skilled motor behaviour using an operant lever-pressing task. Foxp2 loss in each region impacted behaviour differently, with striatal and Purkinje cell disruptions affecting the variability and the speed of lever-press sequences, respectively. Mice lacking Foxp2 in Purkinje cells showed a prominent phenotype involving slowed lever pressing as well as deficits in skilled locomotion. In vivo recordings from Purkinje cells uncovered an increased simple spike firing rate and decreased modulation of firing during limb movements. This was caused by increased intrinsic excitability rather than changes in excitatory or inhibitory inputs. Our findings show that Foxp2 can modulate different aspects of motor behaviour in distinct brain regions, and uncover an unknown role for Foxp2 in the modulation of Purkinje cell activity that severely impacts skilled movements.
  • Gialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Brandler, W., Honbolygó, F., Tóth, D., Csépe, V., Huguet, G., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C., Olson, R. K., Smith, S. D., Pennington, B. F., Vaessen, A., Maurer, U., Lyytinen, H., Peyrard-Janvid, M., Leppänen, P. H. T., Brandeis, D., Bonte, M., Stein, J. F., Talcott, J. B., Fauchereau, F., Wilcke, A., Francks, C., Bourgeron, T., Monaco, A. P., Ramus, F., Landerl, K., Kere, J., Scerri, T. S., Paracchini, S., Fisher, S. E., Schumacher, J., Nöthen, M. M., Müller-Myhsok, B., & Schulte-Körne, G. (2019). Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia. Translational Psychiatry, 9(1): 77. doi:10.1038/s41398-019-0402-0.

    Abstract

    Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
  • Gunz, P., Tilot, A. K., Wittfeld, K., Teumer, A., Shapland, C. Y., Van Erp, T. G. M., Dannemann, M., Vernot, B., Neubauer, S., Guadalupe, T., Fernandez, G., Brunner, H., Enard, W., Fallon, J., Hosten, N., Völker, U., Profico, A., Di Vincenzo, F., Manzi, G., Kelso, J., St Pourcain, B., Hublin, J.-J., Franontike, B., Pääbo, S., Macciardi, F., Grabe, H. J., & Fisher, S. E. (2019). Neandertal introgression sheds light on modern human endocranial globularity. Current Biology, 29(1), 120-127. doi:10.1016/j.cub.2018.10.065.

    Abstract

    One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1-4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4,5]. However, in the absence of fossil brain tissue the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives, the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non- Africans [6,7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural magnetic resonance imaging (MRI) scans of thousands of modern humans, and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.

    Supplementary material

    mmc1.pdf mmc2.xlsx
  • Haworth, S., Shapland, C. Y., Hayward, C., Prins, B. P., Felix, J. F., Medina-Gomez, C., Rivadeneira, F., Wang, C., Ahluwalia, T. S., Vrijheid, M., Guxens, M., Sunyer, J., Tachmazidou, I., Walter, K., Iotchkova, V., Jackson, A., Cleal, L., Huffmann, J., Min, J. L., Sass, L., Timmers, P. R. H. J., UK10K consortium, Davey Smith, G., Fisher, S. E., Wilson, J. F., Cole, T. J., Fernandez-Orth, D., Bønnelykke, K., Bisgaard, H., Pennell, C. E., Jaddoe, V. W. V., Dedoussis, G., Timpson, N. J., Zeggini, E., Vitart, V., & St Pourcain, B. (2019). Low-frequency variation in TP53 has large effects on head circumference and intracranial volume. Nature Communications, 10: 357. doi:10.1038/s41467-018-07863-x.

    Abstract

    Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences affecting these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic influences and low-frequency genetic variation. To understand these influences, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV+HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

    Supplementary material

    Supplementary Information
  • Snijders Blok, L., Kleefstra, T., Venselaar, H., Maas, S., Kroes, H. Y., Lachmeijer, A. M. A., Van Gassen, K. L. I., Firth, H. V., Tomkins, S., Bodek, S., The DDD Study, Õunap, K., Wojcik, M. H., Cunniff, C., Bergstrom, K., Powis, Z., Tang, S., Shinde, D. N., Au, C., Iglesias, A. D., Izumi, K., Leonard, J., Tayoun, A. A., Baker, S. W., Tartaglia, M., Niceta, M., Dentici, M. L., Okamoto, N., Miyake, N., Matsumoto, N., Vitobello, A., Faivre, L., Philippe, C., Gilissen, C., Wiel, L., Pfundt, R., Derizioti, P., Brunner, H. G., & Fisher, S. E. (2019). De novo variants disturbing the transactivation capacity of POU3F3 cause a characteristic neurodevelopmental disorder. The American Journal of Human Genetics, 105(2), 403-412. doi:10.1016/j.ajhg.2019.06.007.

    Abstract

    POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.
  • Truong, D. T., Adams, A. K., Paniagua, S., Frijters, J. C., Boada, R., Hill, D. E., Lovett, M. W., Mahone, E. M., Willcutt, E. G., Wolf, M., Defries, J. C., Gialluisi, A., Francks, C., Fisher, S. E., Olson, R. K., Pennington, B. F., Smith, S. D., Bosson-Heenan, J., & Gruen, J. R. (2019). Multivariate genome-wide association study of rapid automatised naming and rapid alternating stimulus in Hispanic American and African–American youth. Journal of Medical Genetics, 56(8), 557-566. doi:10.1136/jmedgenet-2018-105874.

    Abstract

    Background Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms. Objective To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach. Methods We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African–American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted. Results Genome-wide significant effects were observed at rs1555839 (p=4.03×10−8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer–promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule. Conclusion This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene–brain–behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

    Supplementary material

    Supplementary data
  • Verhoef, E., Demontis, D., Burgess, S., Shapland, C. Y., Dale, P. S., Okbay, A., Neale, B. M., Faraone, S. V., iPSYCH-Broad-PGC ADHD Consortium, Stergiakouli, E., Davey Smith, G., Fisher, S. E., Borglum, A., & St Pourcain, B. (2019). Disentangling polygenic associations between Attention-Deficit/Hyperactivity Disorder, educational attainment, literacy and language. Translational Psychiatry, 9: 35. doi:10.1038/s41398-018-0324-2.

    Abstract

    Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.

    Supplementary material

    41398_2018_324_MOESM1_ESM.docx
  • Becker, M., Devanna, P., Fisher, S. E., & Vernes, S. C. (2018). Mapping of Human FOXP2 Enhancers Reveals Complex Regulation. Frontiers in Molecular Neuroscience, 11: 47. doi:10.3389/fnmol.2018.00047.

    Abstract

    Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators – FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders.
  • Den Hoed, J., Sollis, E., Venselaar, H., Estruch, S. B., Derizioti, P., & Fisher, S. E. (2018). Functional characterization of TBR1 variants in neurodevelopmental disorder. Scientific Reports, 8: 14279. doi:10.1038/s41598-018-32053-6.

    Abstract

    Recurrent de novo variants in the TBR1 transcription factor are implicated in the etiology of sporadic autism spectrum disorders (ASD). Disruptions include missense variants located in the T-box DNA-binding domain and previous work has demonstrated that they disrupt TBR1 protein function. Recent screens of thousands of simplex families with sporadic ASD cases uncovered additional T-box variants in TBR1 but their etiological relevance is unclear. We performed detailed functional analyses of de novo missense TBR1 variants found in the T-box of ASD cases, assessing many aspects of protein function, including subcellular localization, transcriptional activity and protein-interactions. Only two of the three tested variants severely disrupted TBR1 protein function, despite in silico predictions that all would be deleterious. Furthermore, we characterized a putative interaction with BCL11A, a transcription factor that was recently implicated in a neurodevelopmental syndrome involving developmental delay and language deficits. Our findings enhance understanding of molecular functions of TBR1, as well as highlighting the importance of functional testing of variants that emerge from next-generation sequencing, to decipher their contributions to neurodevelopmental disorders like ASD.

    Supplementary material

    Electronic supplementary material
  • Devanna, P., Chen, X. S., Ho, J., Gajewski, D., Smith, S. D., Gialluisi, A., Francks, C., Fisher, S. E., Newbury, D. F., & Vernes, S. C. (2018). Next-gen sequencing identifies non-coding variation disrupting miRNA binding sites in neurological disorders. Molecular Psychiatry, 23(5), 1375-1384. doi:10.1038/mp.2017.30.

    Abstract

    Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3′UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease

    Supplementary material

    mp201730x1.docx
  • Estruch, S. B., Graham, S. A., Quevedo, M., Vino, A., Dekkers, D. H. W., Deriziotis, P., Sollis, E., Demmers, J., Poot, R. A., & Fisher, S. E. (2018). Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders. Human Molecular Genetics, 27(7), 1212-1227. doi:10.1093/hmg/ddy035.

    Abstract

    FOXP transcription factors play important roles in neurodevelopment, but little is known about how their transcriptional activity is regulated. FOXP proteins cooperatively regulate gene expression by forming homo- and hetero-dimers with each other. Physical associations with other transcription factors might also modulate the functions of FOXP proteins. However, few FOXP-interacting transcription factors have been identified so far. Therefore, we sought to discover additional transcription factors that interact with the brain-expressed FOXP proteins, FOXP1, FOXP2 and FOXP4, through affinity-purifications of protein complexes followed by mass spectrometry. We identified seven novel FOXP-interacting transcription factors (NR2F1, NR2F2, SATB1, SATB2, SOX5, YY1 and ZMYM2), five of which have well-estabslished roles in cortical development. Accordingly, we found that these transcription factors are co-expressed with FoxP2 in the deep layers of the cerebral cortex and also in the Purkinje cells of the cerebellum, suggesting that they may cooperate with the FoxPs to regulate neural gene expression in vivo. Moreover, we demonstrated that etiological mutations of FOXP1 and FOXP2, known to cause neurodevelopmental disorders, severely disrupted the interactions with FOXP-interacting transcription factors. Additionally, we pinpointed specific regions within FOXP2 sequence involved in mediating these interactions. Thus, by expanding the FOXP interactome we have uncovered part of a broader neural transcription factor network involved in cortical development, providing novel molecular insights into the transcriptional architecture underlying brain development and neurodevelopmental disorders
  • Gingras, B., Honing, H., Peretz, I., Trainor, L. J., & Fisher, S. E. (2018). Defining the biological bases of individual differences in musicality. In H. Honing (Ed.), The origins of musicality (pp. 221-250). Cambridge, MA: MIT Press.
  • Kong, X., Mathias, S. R., Guadalupe, T., ENIGMA Laterality Working Group, Glahn, D. C., Franke, B., Crivello, F., Tzourio-Mazoyer, N., Fisher, S. E., Thompson, P. M., & Francks, C. (2018). Mapping Cortical Brain Asymmetry in 17,141 Healthy Individuals Worldwide via the ENIGMA Consortium. Proceedings of the National Academy of Sciences of the United States of America, 115(22), E5154-E5163. doi:10.1073/pnas.1718418115.

    Abstract

    Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.

    Supplementary material

    pnas.1718418115.sapp.pdf
  • De Kovel, C. G. F., & Fisher, S. E. (2018). Molecular genetic methods. In A. M. B. De Groot, & P. Hagoort (Eds.), Research methods in psycholinguistics and the neurobiology of language: A practical guide (pp. 330-353). Hoboken: Wiley.
  • De Kovel, C. G. F., Lisgo, S. N., Fisher, S. E., & Francks, C. (2018). Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains. Scientific Reports, 8: 12606. doi:10.1038/s41598-018-29496-2.

    Abstract

    Left-right laterality is an important aspect of human –and in fact all vertebrate– brain organization for which the genetic basis is poorly understood. Using RNA sequencing data we contrasted gene expression in left- and right-sided samples from several structures of the anterior central nervous systems of post mortem human embryos and foetuses. While few individual genes stood out as significantly lateralized, most structures showed evidence of laterality of their overall transcriptomic profiles. These left-right differences showed overlap with age-dependent changes in expression, indicating lateralized maturation rates, but not consistently in left-right orientation over all structures. Brain asymmetry may therefore originate in multiple locations, or if there is a single origin, it is earlier than 5 weeks post conception, with structure-specific lateralized processes already underway by this age. This pattern is broadly consistent with the weak correlations reported between various aspects of adult brain laterality, such as language dominance and handedness.
  • Kuerbitz, J., Arnett, M., Ehrman, S., Williams, M. T., Voorhees, C. V., Fisher, S. E., Garratt, A. N., Muglia, L. J., Waclaw, R. R., & Campbell, K. (2018). Loss of intercalated cells (ITCs) in the mouse amygdala of Tshz1 mutants correlates with fear, depression and social interaction phenotypes. The Journal of Neuroscience, 38, 1160-1177. doi:10.1523/JNEUROSCI.1412-17.2017.

    Abstract

    The intercalated cells (ITCs) of the amygdala have been shown to be critical regulatory components of amygdalar circuits, which control appropriate fear responses. Despite this, the molecular processes guiding ITC development remain poorly understood. Here we establish the zinc finger transcription factor Tshz1 as a marker of ITCs during their migration from the dorsal lateral ganglionic eminence through maturity. Using germline and conditional knock-out (cKO) mouse models, we show that Tshz1 is required for the proper migration and differentiation of ITCs. In the absence of Tshz1, migrating ITC precursors fail to settle in their stereotypical locations encapsulating the lateral amygdala and BLA. Furthermore, they display reductions in the ITC marker Foxp2 and ectopic persistence of the dorsal lateral ganglionic eminence marker Sp8. Tshz1 mutant ITCs show increased cell death at postnatal time points, leading to a dramatic reduction by 3 weeks of age. In line with this, Foxp2-null mutants also show a loss of ITCs at postnatal time points, suggesting that Foxp2 may function downstream of Tshz1 in the maintenance of ITCs. Behavioral analysis of male Tshz1 cKOs revealed defects in fear extinction as well as an increase in floating during the forced swim test, indicative of a depression-like phenotype. Moreover, Tshz1 cKOs display significantly impaired social interaction (i.e., increased passivity) regardless of partner genetics. Together, these results suggest that Tshz1 plays a critical role in the development of ITCs and that fear, depression-like and social behavioral deficits arise in their absence. SIGNIFICANCE STATEMENT We show here that the zinc finger transcription factor Tshz1 is expressed during development of the intercalated cells (ITCs) within the mouse amygdala. These neurons have previously been shown to play a crucial role in fear extinction. Tshz1 mouse mutants exhibit severely reduced numbers of ITCs as a result of abnormal migration, differentiation, and survival of these neurons. Furthermore, the loss of ITCs in mouse Tshz1 mutants correlates well with defects in fear extinction as well as the appearance of depression-like and abnormal social interaction behaviors reminiscent of depressive disorders observed in human patients with distal 18q deletions, including the Tshz1 locus.
  • Xu, S., Liu, P., Chen, Y., Chen, Y., Zhang, W., Zhao, H., Cao, Y., Wang, F., Jiang, N., Lin, S., Li, B., Zhang, Z., Wei, Z., Fan, Y., Jin, Y., He, L., Zhou, R., Dekker, J. D., Tucker, H. O., Fisher, S. E., Yao, Z., Liu, Q., Xia, X., & Guo, X. (2018). Foxp2 regulates anatomical features that may be relevant for vocal behaviors and bipedal locomotion. Proceedings of the National Academy of Sciences of the United States of America, 115(35), 8799-8804. doi:10.1073/pnas.1721820115.

    Abstract

    Fundamental human traits, such as language and bipedalism, are associated with a range of anatomical adaptations in craniofacial shaping and skeletal remodeling. However, it is unclear how such morphological features arose during hominin evolution. FOXP2 is a brain-expressed transcription factor implicated in a rare disorder involving speech apraxia and language impairments. Analysis of its evolutionary history suggests that this gene may have contributed to the emergence of proficient spoken language. In the present study, through analyses of skeleton-specific knockout mice, we identified roles of Foxp2 in skull shaping and bone remodeling. Selective ablation of Foxp2 in cartilage disrupted pup vocalizations in a similar way to that of global Foxp2 mutants, which may be due to pleiotropic effects on craniofacial morphogenesis. Our findings also indicate that Foxp2 helps to regulate strength and length of hind limbs and maintenance of joint cartilage and intervertebral discs, which are all anatomical features that are susceptible to adaptations for bipedal locomotion. In light of the known roles of Foxp2 in brain circuits that are important for motor skills and spoken language, we suggest that this gene may have been well placed to contribute to coevolution of neural and anatomical adaptations related to speech and bipedal locomotion.

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  • Mei, C., Fedorenko, E., Amor, D. J., Boys, A., Hoeflin, C., Carew, P., Burgess, T., Fisher, S. E., & Morgan, A. T. (2018). Deep phenotyping of speech and language skills in individuals with 16p11.2 deletion. European journal of human genetics, 26(5), 676-686. doi:10.1038/s41431-018-0102-x.

    Abstract

    Recurrent deletions of a ~600-kb region of 16p11.2 have been associated with a highly penetrant form of childhood apraxia of speech (CAS). Yet prior findings have been based on a small, potentially biased sample using retrospectively collected data. We examine the prevalence of CAS in a larger cohort of individuals with 16p11.2 deletion using a prospectively designed assessment battery. The broader speech and language phenotype associated with carrying this deletion was also examined. 55 participants with 16p11.2 deletion (47 children, 8 adults) underwent deep phenotyping to test for the presence of CAS and other speech and language diagnoses. Standardized tests of oral motor functioning, speech production, language, and non-verbal IQ were conducted. The majority of children (77%) and half of adults (50%) met criteria for CAS. Other speech outcomes were observed including articulation or phonological errors (i.e., phonetic and cognitive-linguistic errors, respectively), dysarthria (i.e., neuromuscular speech disorder), minimal verbal output, and even typical speech in some. Receptive and expressive language impairment was present in 73% and 70% of children, respectively. Co-occurring neurodevelopmental conditions (e.g., autism) and non-verbal IQ did not correlate with the presence of CAS. Findings indicate that CAS is highly prevalent in children with 16p11.2 deletion with symptoms persisting into adulthood for many. Yet CAS occurs in the context of a broader speech and language profile and other neurobehavioral deficits. Further research will elucidate specific genetic and neural pathways leading to speech and language deficits in individuals with 16p11.2 deletions, resulting in more targeted speech therapies addressing etiological pathways.
  • Morgan, A. T., van Haaften, L., van Hulst, K., Edley, C., Mei, C., Tan, T. Y., Amor, D., Fisher, S. E., & Koolen, D. A. (2018). Early speech development in Koolen de Vries syndrome limited by oral praxis and hypotonia. European journal of human genetics, 26, 75-84. doi:10.1038/s41431-017-0035-9.

    Abstract

    Communication disorder is common in Koolen de Vries syndrome (KdVS), yet its specific symptomatology has not been examined, limiting prognostic counselling and application of targeted therapies. Here we examine the communication phenotype associated with KdVS. Twenty-nine participants (12 males, 4 with KANSL1 variants, 25 with 17q21.31 microdeletion), aged 1.0–27.0 years were assessed for oral-motor, speech, language, literacy, and social functioning. Early history included hypotonia and feeding difficulties. Speech and language development was delayed and atypical from onset of first words (2; 5–3; 5 years of age on average). Speech was characterised by apraxia (100%) and dysarthria (93%), with stuttering in some (17%). Speech therapy and multi-modal communication (e.g., sign-language) was critical in preschool. Receptive and expressive language abilities were typically commensurate (79%), both being severely affected relative to peers. Children were sociable with a desire to communicate, although some (36%) had pragmatic impairments in domains, where higher-level language was required. A common phenotype was identified, including an overriding ‘double hit’ of oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development. Remarkably however, speech prognosis was positive; apraxia resolved, and although dysarthria persisted, children were intelligible by mid-to-late childhood. In contrast, language and literacy deficits persisted, and pragmatic deficits were apparent. Children with KdVS require early, intensive, speech motor and language therapy, with targeted literacy and social language interventions as developmentally appropriate. Greater understanding of the linguistic phenotype may help unravel the relevance of KANSL1 to child speech and language development.

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    41431_2017_35_MOESM1_ESM.docx
  • St Pourcain, B., Robinson, E. B., Anttila, V., Sullivan, B. B., Maller, J., Golding, J., Skuse, D., Ring, S., Evans, D. M., Zammit, S., Fisher, S. E., Neale, B. M., Anney, R., Ripke, S., Hollegaard, M. V., Werge, T., iPSYCH-SSI-Broad Autism Group, Ronald, A., Grove, J., Hougaard, D. M., Børglum, A. D., Mortensen, P. B., Daly, M., & Davey Smith, G. (2018). ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social-communication difficulties. Molecular Psychiatry, 23, 263-270. doi:10.1038/mp.2016.198.

    Abstract

    Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic in fluences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children,N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic in fluences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors in fluencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic in fluences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms

    Supplementary material

    mp2016198x1.docx
  • St Pourcain, B., Eaves, L. J., Ring, S. M., Fisher, S. E., Medland, S., Evans, D. M., & Smith, G. D. (2018). Developmental changes within the genetic architecture of social communication behaviour: A multivariate study of genetic variance in unrelated individuals. Biological Psychiatry, 83(7), 598-606. doi:10.1016/j.biopsych.2017.09.020.

    Abstract

    Background: Recent analyses of trait-disorder overlap suggest that psychiatric dimensions may relate to distinct sets of genes that exert their maximum influence during different periods of development. This includes analyses of social-communciation difficulties that share, depending on their developmental stage, stronger genetic links with either Autism Spectrum Disorder or schizophrenia. Here we developed a multivariate analysis framework in unrelated individuals to model directly the developmental profile of genetic influences contributing to complex traits, such as social-communication difficulties, during a ~10-year period spanning childhood and adolescence. Methods: Longitudinally assessed quantitative social-communication problems (N ≤ 5,551) were studied in participants from a UK birth cohort (ALSPAC, 8 to 17 years). Using standardised measures, genetic architectures were investigated with novel multivariate genetic-relationship-matrix structural equation models (GSEM) incorporating whole-genome genotyping information. Analogous to twin research, GSEM included Cholesky decomposition, common pathway and independent pathway models. Results: A 2-factor Cholesky decomposition model described the data best. One genetic factor was common to SCDC measures across development, the other accounted for independent variation at 11 years and later, consistent with distinct developmental profiles in trait-disorder overlap. Importantly, genetic factors operating at 8 years explained only ~50% of the genetic variation at 17 years. Conclusion: Using latent factor models, we identified developmental changes in the genetic architecture of social-communication difficulties that enhance the understanding of ASD and schizophrenia-related dimensions. More generally, GSEM present a framework for modelling shared genetic aetiologies between phenotypes and can provide prior information with respect to patterns and continuity of trait-disorder overlap
  • Snijders Blok, L., Hiatt, S. M., Bowling, K. M., Prokop, J. W., Engel, K. L., Cochran, J. N., Bebin, E. M., Bijlsma, E. K., Ruivenkamp, C. A. L., Terhal, P., Simon, M. E. H., Smith, R., Hurst, J. A., The DDD study, MCLaughlin, H., Person, R., Crunk, A., Wangler, M. F., Streff, H., Symonds, J. D., Zuberi, S. M., Elliott, K. S., Sanders, V. R., Masunga, A., Hopkin, R. J., Dubbs, H. A., Ortiz-Gonzalez, X. R., Pfundt, R., Brunner, H. G., Fisher, S. E., Kleefstra, T., & Cooper, G. M. (2018). De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder. Human Genetics, 137(5), 375-388. doi:10.1007/s00439-018-1887-y.

    Abstract

    Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes
  • Snijders Blok, L., Rousseau, J., Twist, J., Ehresmann, S., Takaku, M., Venselaar, H., Rodan, L. H., Nowak, C. B., Douglas, J., Swoboda, K. J., Steeves, M. A., Sahai, I., Stumpel, C. T. R. M., Stegmann, A. P. A., Wheeler, P., Willing, M., Fiala, E., Kochhar, A., Gibson, W. T., Cohen, A. S. A., Agbahovbe, R., Innes, A. M., Au, P. Y. B., Rankin, J., Anderson, I. J., Skinner, S. A., Louie, R. J., Warren, H. E., Afenjar, A., Keren, B., Nava, C., Buratti, J., Isapof, A., Rodriguez, D., Lewandowski, R., Propst, J., Van Essen, T., Choi, M., Lee, S., Chae, J. H., Price, S., Schnur, R. E., Douglas, G., Wentzensen, I. M., Zweier, C., Reis, A., Bialer, M. G., Moore, C., Koopmans, M., Brilstra, E. H., Monroe, G. R., Van Gassen, K. L. I., Van Binsbergen, E., Newbury-Ecob, R., Bownass, L., Bader, I., Mayr, J. A., Wortmann, S. B., Jakielski, K. J., Strand, E. A., Kloth, K., Bierhals, T., The DDD study, Roberts, J. D., Petrovich, R. M., Machida, S., Kurumizaka, H., Lelieveld, S., Pfundt, R., Jansen, S., Derizioti, P., Faivre, L., Thevenon, J., Assoum, M., Shriberg, L., Kleefstra, T., Brunner, H. G., Wade, P. A., Fisher, S. E., & Campeau, P. M. (2018). CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. Nature Communications, 9: 4619. doi:10.1038/s41467-018-06014-6.

    Abstract

    Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.
  • Sønderby, I. E., Gústafsson, Ó., Doan, N. T., Hibar, D. P., Martin-Brevet, S., Westlye, L. T., Jacquemont, S., Djurovic, S., Stefánsson, H., Stefánsson, K., Thompson, P. M., Andreassen, O. A., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N., Blangero, J., Boomsma, D. I., Bralten, J., Brattbak, H.-R., Brodaty, H., Brouwer, R. M., Bülow, R., Calhoun, V., Caspers, S., Cavalleri, G., Chen, C.-H., Cichon, S., Ciufolini, S., Corvin, A., Crespo-Facorro, B., Curran, J. E., Dale, A. M., Dalvie, S., Dazzan, P., de Geus, E. J., de Zubicaray, G. I., de Zwarte, S. M., Delanty, N., den Braber, A., Desrivières, S., Donohoe, G., Draganski, B., Ehrlich, S., Espeseth, T., Fisher, S. E., Franke, B., Frouin, V., Fukunaga, M., Gareau, T., Glahn, D. C., Grabe, H., Groenewold, N. A., Haavik, J., Håberg, A., Hashimoto, R., Hehir-Kwa, J. Y., Heinz, A., Hillegers, M. H., Hoffmann, P., Holleran, L., Hottenga, J.-J., Hulshoff, H. E., Ikeda, M., Jahanshad, N., Jernigan, T., Jockwitz, C., Johansson, S., Jonsdottir, G. A., Jönsson, E. G., Kahn, R., Kaufmann, T., Kelly, S., Kikuchi, M., Knowles, E. E., Kolskår, K. K., Kwok, J. B., Le Hellard, S., Leu, C., Liu, J., Lundervold, A. J., Lundervold, A., Martin, N. G., Mather, K., Mathias, S. R., McCormack, M., McMahon, K. L., McRae, A., Milaneschi, Y., Moreau, C., Morris, D., Mothersill, D., Mühleisen, T. W., Murray, R., Nordvik, J. E., Nyberg, L., Loohuis, L. M. O., Ophoff, R., Paus, T., Pausova, Z., Penninx, B., Peralta, J. M., Pike, B., Prieto, C., Pudas, S., Quinlan, E., Quintana, D. S., Reinbold, C. S., Marques, T. R., Reymond, A., Richard, G., Rodriguez-Herreros, B., Roiz-Santiañez, R., Rucker, J., Sachdev, P., Sanders, A.-M., Sando, S. B., Schmaal, L., Schofield, P. R., Schork, A. J., Schumann, G., Shin, J., Shumskaya, E., Sisodiya, S., Steen, V. M., Stein, D. J., Steinberg, S., Strike, L., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J., Ueland, T., Uhlmann, A., Ulfarsson, M. O., van Ent, D. '., van der Meer, D., van Haren, N. E., Vaskinn, A., Vassos, E., Walters, G. B., Wang, Y., Wen, W., Whelan, C. D., Wittfeld, K., Wright, M., Yamamori, H., Zayats, T., & Agartz, I. (2018). Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia. Molecular Psychiatry. Advance online publication. doi:10.1038/s41380-018-0118-1.

    Abstract

    Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes
  • Tilot, A. K., Kucera, K. S., Vino, A., Asher, J. E., Baron-Cohen, S., & Fisher, S. E. (2018). Rare variants in axonogenesis genes connect three families with sound–color synesthesia. Proceedings of the National Academy of Sciences of the United States of America, 115(12), 3168-3173. doi:10.1073/pnas.1715492115.

    Abstract

    Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound–color (auditory–visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes—COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2—associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences.

    Supplementary material

    Tilot_etal_2018SI.pdf
  • Van der Meer, D., Rokicki, J., Kaufmann, T., Córdova-Palomera, A., Moberget, T., Alnæs, D., Bettella, F., Frei, O., Trung Doan, N., Sønderby, I. E., Smeland, O. B., Agartz, I., Bertolino, A., Bralten, J., Brandt, C. L., Buitelaar, J. K., Djurovic, S., Van Donkelaar, M. M. J., Dørum, E. S., Espeseth, T., Faraone, S. V., Fernandez, G., Fisher, S. E., Franke, B., Haatveit, B., Hartman, C., Hoekstra, P. J., Haberg, A. K., Jönsson, E. G., Kolskår, K. K., Le Hellard, S., Lund, M. J., Lundervold, A. J., Lundervold, A., Melle, I., Monereo Sánchez, J., Norbom, L. C., Nordvik, J. E., Nyberg, L., Oosterlaan, J., Papalino, M., Papassotiropoulos, A., Pergola, G., De Quervain, D. J. F., Richard, G., Sanders, A.-M., Selvaggi, P., Shumskaya, E., Steen, V. M., Tønnesen, S., Ulrichsen, K. M., Zwiers, M., Andreassen, O. A., & Westlye, L. T. (2018). Brain scans from 21297 individuals reveal the genetic architecture of hippocampal subfield volumes. Molecular Psychiatry. Advance online publication. doi:10.1038/s41380-018-0262-7.

    Abstract

    The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer’s disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields’ genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10–16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

    Supplementary material

    41380_2018_262_MOESM1_ESM.docx
  • Van Rhijn, J. R., Fisher, S. E., Vernes, S. C., & Nadif Kasri, N. (2018). Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release. Brain Structure and Function, 223(9), 4211-4226. doi:10.1007/s00429-018-1746-6.

    Abstract

    Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced Foxp2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of Foxp2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-mediated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced Foxp2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous Foxp2 mice. Our results suggest a novel role for Foxp2 in the regulation of striatal direct pathway activity through managing inhibitory drive.

    Supplementary material

    429_2018_1746_MOESM1_ESM.docx
  • Acuna-Hidalgo, R., Deriziotis, P., Steehouwer, M., Gilissen, C., Graham, S. A., Van Dam, S., Hoover-Fong, J., Telegrafi, A. B., Destree, A., Smigiel, R., Lambie, L. A., Kayserili, H., Altunoglu, U., Lapi, E., Uzielli, M. L., Aracena, M., Nur, B. G., Mihci, E., Moreira, L. M. A., Ferreira, V. B., Horovitz, D. D. G., Da Rocha, K. M., Jezela-Stanek, A., Brooks, A. S., Reutter, H., Cohen, J. S., Fatemi, A., Smitka, M., Grebe, T. A., Di Donato, N., Deshpande, C., Vandersteen, A., Marques Lourenço, C., Dufke, A., Rossier, E., Andre, G., Baumer, A., Spencer, C., McGaughran, J., Franke, L., Veltman, J. A., De Vries, B. B. A., Schinzel, A., Fisher, S. E., Hoischen, A., & Van Bon, B. W. (2017). Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. PLoS Genetics, 13: e1006683. doi:10.1371/journal.pgen.1006683.

    Abstract

    Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
  • Carrion Castillo, A., Maassen, B., Franke, B., Heister, A., Naber, M., Van der Leij, A., Francks, C., & Fisher, S. E. (2017). Association analysis of dyslexia candidate genes in a Dutch longitudinal sample. European Journal of Human Genetics, 25(4), 452-460. doi:10.1038/ejhg.2016.194.

    Abstract

    Dyslexia is a common specific learning disability with a substantive genetic component. Several candidate genes have been proposed to be implicated in dyslexia susceptibility, such as DYX1C1, ROBO1, KIAA0319, and DCDC2. Associations with variants in these genes have also been reported with a variety of psychometric measures tapping into the underlying processes that might be impaired in dyslexic people. In this study, we first conducted a literature review to select single nucleotide polymorphisms (SNPs) in dyslexia candidate genes that had been repeatedly implicated across studies. We then assessed the SNPs for association in the richly phenotyped longitudinal data set from the Dutch Dyslexia Program. We tested for association with several quantitative traits, including word and nonword reading fluency, rapid naming, phoneme deletion, and nonword repetition. In this, we took advantage of the longitudinal nature of the sample to examine if associations were stable across four educational time-points (from 7 to 12 years). Two SNPs in the KIAA0319 gene were nominally associated with rapid naming, and these associations were stable across different ages. Genetic association analysis with complex cognitive traits can be enriched through the use of longitudinal information on trait development.
  • Chen, X. S., Reader, R. H., Hoischen, A., Veltman, J. A., Simpson, N. H., Francks, C., Newbury, D. F., & Fisher, S. E. (2017). Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment. Scientific Reports, 7: 46105. doi:10.1038/srep46105.

    Abstract

    A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential “multiple-hit” cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation.
  • Deriziotis, P., & Fisher, S. E. (2017). Speech and Language: Translating the Genome. Trends in Genetics, 33(9), 642-656. doi:10.1016/j.tig.2017.07.002.

    Abstract

    Investigation of the biological basis of human speech and language is being transformed by developments in molecular technologies, including high-throughput genotyping and next-generation sequencing of whole genomes. These advances are shedding new light on the genetic architecture underlying language-related disorders (speech apraxia, specific language impairment, developmental dyslexia) as well as that contributing to variation in relevant skills in the general population. We discuss how state-of-the-art methods are uncovering a range of genetic mechanisms, from rare mutations of large effect to common polymorphisms that increase risk in a subtle way, while converging on neurogenetic pathways that are shared between distinct disorders. We consider the future of the field, highlighting the unusual challenges and opportunities associated with studying genomics of language-related traits.
  • Fisher, S. E. (2017). Evolution of language: Lessons from the genome. Psychonomic Bulletin & Review, 24(1), 34-40. doi: 10.3758/s13423-016-1112-8.

    Abstract

    The post-genomic era is an exciting time for researchers interested in the biology of speech and language. Substantive advances in molecular methodologies have opened up entire vistas of investigation that were not previously possible, or in some cases even imagined. Speculations concerning the origins of human cognitive traits are being transformed into empirically addressable questions, generating specific hypotheses that can be explicitly tested using data collected from both the natural world and experimental settings. In this article, I discuss a number of promising lines of research in this area. For example, the field has begun to identify genes implicated in speech and language skills, including not just disorders but also the normal range of abilities. Such genes provide powerful entry points for gaining insights into neural bases and evolutionary origins, using sophisticated experimental tools from molecular neuroscience and developmental neurobiology. At the same time, sequencing of ancient hominin genomes is giving us an unprecedented view of the molecular genetic changes that have occurred during the evolution of our species. Synthesis of data from these complementary sources offers an opportunity to robustly evaluate alternative accounts of language evolution. Of course, this endeavour remains challenging on many fronts, as I also highlight in the article. Nonetheless, such an integrated approach holds great potential for untangling the complexities of the capacities that make us human.
  • Gialluisi, A., Guadalupe, T., Francks, C., & Fisher, S. E. (2017). Neuroimaging genetic analyses of novel candidate genes associated with reading and language. Brain and Language, 172, 9-15. doi:10.1016/j.bandl.2016.07.002.

    Abstract

    Neuroimaging measures provide useful endophenotypes for tracing genetic effects on reading and language. A recent Genome-Wide Association Scan Meta-Analysis (GWASMA) of reading and language skills (N = 1862) identified strongest associations with the genes CCDC136/FLNC and RBFOX2. Here, we follow up the top findings from this GWASMA, through neuroimaging genetics in an independent sample of 1275 healthy adults. To minimize multiple-testing, we used a multivariate approach, focusing on cortical regions consistently implicated in prior literature on developmental dyslexia and language impairment. Specifically, we investigated grey matter surface area and thickness of five regions selected a priori: middle temporal gyrus (MTG); pars opercularis and pars triangularis in the inferior frontal gyrus (IFG-PO and IFG-PT); postcentral parietal gyrus (PPG) and superior temporal gyrus (STG). First, we analysed the top associated polymorphisms from the reading/language GWASMA: rs59197085 (CCDC136/FLNC) and rs5995177 (RBFOX2). There was significant multivariate association of rs5995177 with cortical thickness, driven by effects on left PPG, right MTG, right IFG (both PO and PT), and STG bilaterally. The minor allele, previously associated with reduced reading-language performance, showed negative effects on grey matter thickness. Next, we performed exploratory gene-wide analysis of CCDC136/FLNC and RBFOX2; no other associations surpassed significance thresholds. RBFOX2 encodes an important neuronal regulator of alternative splicing. Thus, the prior reported association of rs5995177 with reading/language performance could potentially be mediated by reduced thickness in associated cortical regions. In future, this hypothesis could be tested using sufficiently large samples containing both neuroimaging data and quantitative reading/language scores from the same individuals.

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  • Guadalupe, T., Mathias, S. R., Van Erp, T. G. M., Whelan, C. D., Zwiers, M. P., Abe, Y., Abramovic, L., Agartz, I., Andreassen, O. A., Arias-Vásquez, A., Aribisala, B. S., Armstrong, N. J., Arolt, V., Artiges, E., Ayesa-Arriola, R., Baboyan, V. G., Banaschewski, T., Barker, G., Bastin, M. E., Baune, B. T., Blangero, J., Bokde, A. L., Boedhoe, P. S., Bose, A., Brem, S., Brodaty, H., Bromberg, U., Brooks, S., Büchel, C., Buitelaar, J., Calhoun, V. D., Cannon, D. M., Cattrell, A., Cheng, Y., Conrod, P. J., Conzelmann, A., Corvin, A., Crespo-Facorro, B., Crivello, F., Dannlowski, U., De Zubicaray, G. I., De Zwarte, S. M., Deary, I. J., Desrivières, S., Doan, N. T., Donohoe, G., Dørum, E. S., Ehrlich, S., Espeseth, T., Fernández, G., Flor, H., Fouche, J.-P., Frouin, V., Fukunaga, M., Gallinat, J., Garavan, H., Gill, M., Suarez, A. G., Gowland, P., Grabe, H. J., Grotegerd, D., Gruber, O., Hagenaars, S., Hashimoto, R., Hauser, T. U., Heinz, A., Hibar, D. P., Hoekstra, P. J., Hoogman, M., Howells, F. M., Hu, H., Hulshoff Pol, H. E.., Huyser, C., Ittermann, B., Jahanshad, N., Jönsson, E. G., Jurk, S., Kahn, R. S., Kelly, S., Kraemer, B., Kugel, H., Kwon, J. S., Lemaitre, H., Lesch, K.-P., Lochner, C., Luciano, M., Marquand, A. F., Martin, N. G., Martínez-Zalacaín, I., Martinot, J.-L., Mataix-Cols, D., Mather, K., McDonald, C., McMahon, K. L., Medland, S. E., Menchón, J. M., Morris, D. W., Mothersill, O., Maniega, S. M., Mwangi, B., Nakamae, T., Nakao, T., Narayanaswaamy, J. C., Nees, F., Nordvik, J. E., Onnink, A. M. H., Opel, N., Ophoff, R., Martinot, M.-L.-P., Orfanos, D. P., Pauli, P., Paus, T., Poustka, L., Reddy, J. Y., Renteria, M. E., Roiz-Santiáñez, R., Roos, A., Royle, N. A., Sachdev, P., Sánchez-Juan, P., Schmaal, L., Schumann, G., Shumskaya, E., Smolka, M. N., Soares, J. C., Soriano-Mas, C., Stein, D. J., Strike, L. T., Toro, R., Turner, J. A., Tzourio-Mazoyer, N., Uhlmann, A., Valdés Hernández, M., Van den Heuvel, O. A., Van der Meer, D., Van Haren, N. E.., Veltman, D. J., Venkatasubramanian, G., Vetter, N. C., Vuletic, D., Walitza, S., Walter, H., Walton, E., Wang, Z., Wardlaw, J., Wen, W., Westlye, L. T., Whelan, R., Wittfeld, K., Wolfers, T., Wright, M. J., Xu, J., Xu, X., Yun, J.-Y., Zhao, J., Franke, B., Thompson, P. M., Glahn, D. C., Mazoyer, B., Fisher, S. E., & Francks, C. (2017). Human subcortical asymmetries in 15,847 people worldwide reveal effects of age and sex. Brain Imaging and Behavior, 11(5), 1497-1514. doi:10.1007/s11682-016-9629-z.

    Abstract

    The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

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    11682_2016_9629_MOESM1_ESM.pdf
  • Hibar, D. P., Adams, H. H. H., Jahanshad, N., Chauhan, G., Stein, J. L., Hofer, E., Rentería, M. E., Bis, J. C., Arias-Vasquez, A., Ikram, M. K., Desrivieres, S., Vernooij, M. W., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B. S., Armstrong, N. J., Athanasiu, L., Axelsson, T., Beecham, A. H., Beiser, A., Bernard, M., Blanton, S. H., Bohlken, M. M., Boks, M. P., Bralten, J., Brickman, A. M., Carmichael, O., Chakravarty, M. M., Chen, Q., Ching, C. R. K., Chouraki, V., Cuellar-Partida, G., Crivello, F., den Brabander, A., Doan, N. T., Ehrlich, S., Giddaluru, S., Goldman, A. L., Gottesman, R. F., Grimm, O., Griswold, M. E., Guadalupe, T., Gutman, B. A., Hass, J., Haukvik, U. K., Hoehn, D., Holmes, A. J., Hoogman, M., Janowitz, D., Jia, T., Jørgensen, K. N., Mirza-Schreiber, N., Kasperaviciute, D., Kim, S., Klein, M., Krämer, B., Lee, P. H., Liewald, D. C. M., Lopez, L. M., Luciano, M., Macare, C., Marquand, A. F., Matarin, M., Mather, K. A., Mattheisen, M., McKay, D. R., Milaneschi, Y., Maniega, S. M., Nho, K., Nugent, A. C., Nyquist, P., Olde Loohuis, L. M., Oosterlaan, J., Papmeyer, M., Pirpamer, L., Pütz, B., Ramasamy, A., Richards, J. S., Risacher, S., Roiz-Santiañez, R., Rommelse, N., Ropele, S., Rose, E., Royle, N. A., Rundek, T., Sämann, P. G., Saremi, A., Satizabal, C. L., Schmaal, L., Schork, A. J., Shen, L., Shin, J., Shumskaya, E., Smith, A. V., Sprooten, E., Strike, L. T., Teumer, A., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Trompet, S., Vaidya, D., Van der Grond, J., Van der Lee, S. J., Van der Meer, D., Van Donkelaar, M. M. J., Van Eijk, K. R., van Erp, T. G. M., Van Rooij, D., Walton, E., Westlye, L. T., Whelan, C. D., Windham, B. G., Winkler, A. M., Wittfeld, K. M., Woldehawariat, G., Wolf, C., Wolfers, T., Yanek, L. R., Yang, J., Zijdenbos, A., Zwiers, M. P., Agartz, I., Almasy, L., Ames, D., Amouyel, P., Andreassen, O. A., Arepalli, S., Assareh, A. A., Barral, S., Bastin, M. E., Becker, D. M., Becker, J. T., Bennett, D. A., Blangero, J., Van Bokhoven, H., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Brunner, H. G., Buckner, R. L., Buitelaar, J. K., Bulayeva, K. B., Cahn, W., Calhoun, V. D., Cannon, D. M., Cavalleri, G. L., Cheng, C.-Y., Cichon, S., Cookson, M. R., Corvin, A., Crespo-Facorro, B., Curran, J. E., Czisch, M., Dale, A. M., Davies, G. E., De Craen, A. J. M., De Geus, E. J. C., De Jager, P. L., De Zubicaray, G. i., Deary, I. J., Debette, S., DeCarli, C., Delanty, N., Depondt, C., DeStefano, A., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W. C., Duggirala, R., Dyer, T. D., Enzinger, C., Erk, S., Espeseth, T., Fedko, I. O., Fernández, G., Ferrucci, L., Fisher, S. E., Fleischman, D. A., Ford, I., Fornage, M., Foroud, T. M., Fox, P. T., Francks, C., Fukunaga, M., Gibbs, J. R., Glahn, D. C., Gollub, R. L., Göring, H. H. H., Green, R. C., Gruber, O., Gudnason, V., Guelfi, S., Haberg, A. K., Hansell, N. K., Hardy, J., Hartman, C. A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D. G., Heslenfeld, D. J., Ho, B.-C., Hoekstra, P. J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J.-J., Huentelman, M., Pol, H. E. H., Ikeda, M., Jack Jr., C. R., Jenkinson, M., Johnson, R., Jonsson, E. G., Jukema, J. W., Kahn, R. S., Kanai, R., Kloszewska, I., Knopman, D. S., Kochunov, P., Kwok, J. B., Lawrie, S. M., Lemaître, H., Liu, X., Longo, D. L., Lopez, O. L., Lovestone, S., Martinez, O., Martinot, J.-L., Mattay, V. S., McDonald, C., Mcintosh, A. M., McMahon, F., McMahon, K. L., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G. W., Morris, D. W., Mosley, T. H., Mühleisen, T. W., Müller-Myhsok, B., Nalls, M. A., Nauck, M., Nichols, T. E., Niessen, W. J., Nöthen, M. M., Nyberg, L., Ohi, K., Olvera, R. L., Ophoff, R. A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B. W. J. H., Pike, G. B., Potkin, S. G., Psaty, B. M., Reppermund, S., Rietschel, M., Roffman, J. L., Romanczuk-Seiferth, N., Rotter, J. I., Ryten, M., Sacco, R. L., Sachdev, P. S., Saykin, A. J., Schmidt, R., Schmidt, H., Schofield, P. R., Sigursson, S., Simmons, A., Singleton, A., Sisodiya, S. M., Smith, C., Smoller, J. W., Soininen, H., Steen, V. M., Stott, D. J., Sussmann, J. E., Thalamuthu, A., Toga, A. W., Traynor, B. J., Troncoso, J., Tsolaki, M., Tzourio, C., Uitterlinden, A. G., Hernández, M. C. V., Van der Brug, M., Van der Lugt, A., Van der Wee, N. J. A., Van Haren, N. E. M., Van Tol, M.-J., Vardarajan, B. N., Vellas, B., Veltman, D. J., Völzke, H., Walter, H., Wardlaw, J. M., Wassink, T. H., Weale, M. e., Weinberger, D. R., Weiner, M., Wen, W., Westman, E., White, T., Wong, T. Y., Wright, C. B., Zielke, R. H., Zonderman, A. B., Martin, N. G., Van Duijn, C. M., Wright, M. J., Longstreth, W. W. T., Schumann, G., Grabe, H. J., Franke, B., Launer, L. J., Medland, S. E., Seshadri, S., Thompson, P. M., & Ikram, A. (2017). Novel genetic loci associated with hippocampal volume. Nature Communications, 8: 13624. doi:10.1038/ncomms13624.

    Abstract

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

    Supplementary material

    ncomms13624-s1.pdf ncomms13624-s2.xlsx
  • Kavaklioglu, T., Guadalupe, T., Zwiers, M., Marquand, A. F., Onnink, M., Shumskaya, E., Brunner, H., Fernandez, G., Fisher, S. E., & Francks, C. (2017). Structural asymmetries of the human cerebellum in relation to cerebral cortical asymmetries and handedness. Brain Structure and Function, 22, 1611-1623. doi:10.1007/s00429-016-1295-9.

    Abstract

    There is evidence that the human cerebellum is involved not only in motor control but also in other cognitive functions. Several studies have shown that language-related activation is lateralized toward the right cerebellar hemisphere in most people, in accordance with leftward cerebral cortical lateralization for language and a general contralaterality of cerebral–cerebellar activations. In terms of behavior, hand use elicits asymmetrical activation in the cerebellum, while hand preference is weakly associated with language lateralization. However, it is not known how, or whether, these functional relations are reflected in anatomy. We investigated volumetric gray matter asymmetries of cerebellar lobules in an MRI data set comprising 2226 subjects. We tested these cerebellar asymmetries for associations with handedness, and for correlations with cerebral cortical anatomical asymmetries of regions important for language or hand motor control, as defined by two different automated image analysis methods and brain atlases, and supplemented with extensive visual quality control. No significant associations of cerebellar asymmetries to handedness were found. Some significant associations of cerebellar lobular asymmetries to cerebral cortical asymmetries were found, but none of these correlations were greater than 0.14, and they were mostly method-/atlas-dependent. On the basis of this large and highly powered study, we conclude that there is no overt structural manifestation of cerebellar functional lateralization and connectivity, in respect of hand motor control or language laterality
  • De Kovel, C. G. F., Lisgo, S., Karlebach, G., Ju, J., Cheng, G., Fisher, S. E., & Francks, C. (2017). Left-right asymmetry of maturation rates in human embryonic neural development. Biological Psychiatry, 82(3), 204-212. doi:10.1016/j.biopsych.2017.01.016.

    Abstract

    Background Left-right asymmetry is a fundamental organizing feature of the human brain, and neuro-psychiatric disorders such as schizophrenia sometimes involve alterations of brain asymmetry. As early as 8 weeks post conception, the majority of human fetuses move their right arms more than their left arms, but because nerve fibre tracts are still descending from the forebrain at this stage, spinal-muscular asymmetries are likely to play an important developmental role. Methods We used RNA sequencing to measure gene expression levels in the left and right spinal cords, and left and right hindbrains, of 18 post-mortem human embryos aged 4-8 weeks post conception. Genes showing embryonic lateralization were tested for an enrichment of signals in genome-wide association data for schizophrenia. Results The left side of the embryonic spinal cord was found to mature faster than the right side. Both sides transitioned from transcriptional profiles associated with cell division and proliferation at earlier stages, to neuronal differentiation and function at later stages, but the two sides were not in synchrony (p = 2.2 E-161). The hindbrain showed a left-right mirrored pattern compared to the spinal cord, consistent with the well-known crossing over of function between these two structures. Genes that showed lateralization in the embryonic spinal cord were enriched for association signals with schizophrenia (p = 4.3 E-05). Conclusions These are the earliest-stage left-right differences of human neural development ever reported. Disruption of the lateralised developmental programme may play a role in the genetic susceptibility to schizophrenia.

    Supplementary material

    mmc1.pdf
  • Sollis, E., Deriziotis, P., Saitsu, H., Miyake, N., Matsumoto, N., J.V.Hoffer, M. J. V., Ruivenkamp, C. A., Alders, M., Okamoto, N., Bijlsma, E. K., Plomp, A. S., & Fisher, S. E. (2017). Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders. Human Mutation, 38(11), 1542-1554. doi:10.1002/humu.23303.

    Abstract

    The closely related paralogues FOXP2 and FOXP1 encode transcription factors with shared functions in the development of many tissues, including the brain. However, while mutations in FOXP2 lead to a speech/language disorder characterized by childhood apraxia of speech (CAS), the clinical profile of FOXP1 variants includes a broader neurodevelopmental phenotype with global developmental delay, intellectual disability and speech/language impairment. Using clinical whole-exome sequencing, we report an identical de novo missense FOXP1 variant identified in three unrelated patients. The variant, p.R514H, is located in the forkhead-box DNA-binding domain and is equivalent to the well-studied p.R553H FOXP2 variant that co-segregates with CAS in a large UK family. We present here for the first time a direct comparison of the molecular and clinical consequences of the same mutation affecting the equivalent residue in FOXP1 and FOXP2. Detailed functional characterization of the two variants in cell model systems revealed very similar molecular consequences, including aberrant subcellular localization, disruption of transcription factor activity and deleterious effects on protein interactions. Nonetheless, clinical manifestations were broader and more severe in the three cases carrying the p.R514H FOXP1 variant than in individuals with the p.R553H variant related to CAS, highlighting divergent roles of FOXP2 and FOXP1 in neurodevelopment.

    Supplementary material

    humu23303-sup-0001-SuppMat.pdf
  • Stergiakouli, E., Smith, G. D., Martin, J., Skuse, D. H., Viechtbauer, W., Ring, S. M., Ronald, A., Evans, D. E., Fisher, S. E., Thapar, A., & St Pourcain, B. (2017). Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development. Molecular Autism, 8: 18. doi:10.1186/s13229-017-0131-2.

    Abstract

    Background: Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk. Methods: Social-communication difficulties (N ≤ 5551, Social and Communication Disorders Checklist, SCDC) and combined hyperactive-impulsive/inattentive ADHD symptoms (N ≤ 5678, Strengths and Difficulties Questionnaire, SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls) were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between phenotypes were estimated using genome-wide data. Results: In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait rg ≤ 1, pmin = 3 × 10−4) as those between repeated measures of the same trait (within-trait rg ≤ 0.94, pmin = 7 × 10−4). Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling upregulated genes (p-meta = 6.4 × 10−4). Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression R2 = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores were linked to genetic risk for disorder. Conclusions: In the general population, genetic aetiologies between social-communication difficulties and ADHD symptoms are shared throughout child and adolescent development and may implicate similar biological pathways that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional trait-disorder relationships.
  • Thompson, P. M., Andreassen, O. A., Arias-Vasquez, A., Bearden, C. E., Boedhoe, P. S., Brouwer, R. M., Buckner, R. L., Buitelaar, J. K., Bulaeva, K. B., Cannon, D. M., Cohen, R. A., Conrod, P. J., Dale, A. M., Deary, I. J., Dennis, E. L., De Reus, M. A., Desrivieres, S., Dima, D., Donohoe, G., Fisher, S. E., Fouche, J.-P., Francks, C., Frangou, S., Franke, B., Ganjgahi, H., Garavan, H., Glahn, D. C., Grabe, H. J., Guadalupe, T., Gutman, B. A., Hashimoto, R., Hibar, D. P., Holland, D., Hoogman, M., Pol, H. E. H., Hosten, N., Jahanshad, N., Kelly, S., Kochunov, P., Kremen, W. S., Lee, P. H., Mackey, S., Martin, N. G., Mazoyer, B., McDonald, C., Medland, S. E., Morey, R. A., Nichols, T. E., Paus, T., Pausova, Z., Schmaal, L., Schumann, G., Shen, L., Sisodiya, S. M., Smit, D. J., Smoller, J. W., Stein, D. J., Stein, J. L., Toro, R., Turner, J. A., Van den Heuvel, M., Van den Heuvel, O. A., Van Erp, T. G., Van Rooij, D., Veltman, D. J., Walter, H., Wang, Y., Wardlaw, J. M., Whelan, C. D., Wright, M. J., & Ye, J. (2017). ENIGMA and the Individual: Predicting Factors that Affect the Brain in 35 Countries Worldwide. NeuroImage, 145, 389-408. doi:10.1016/j.neuroimage.2015.11.057.
  • Udden, J., Snijders, T. M., Fisher, S. E., & Hagoort, P. (2017). A common variant of the CNTNAP2 gene is associated with structural variation in the left superior occipital gyrus. Brain and Language, 172, 16-21. doi:10.1016/j.bandl.2016.02.003.

    Abstract

    The CNTNAP2 gene encodes a cell-adhesion molecule that influences the properties of neural networks and the morphology and density of neurons and glial cells. Previous studies have shown association of CNTNAP2 variants with language-related phenotypes in health and disease. Here, we report associations of a common CNTNAP2 polymorphism (rs7794745) with variation in grey matter in a region in the dorsal visual stream. We tried to replicate an earlier study on 314 subjects by Tan and colleagues (2010), but now in a substantially larger group of more than 1700 subjects. Carriers of the T allele showed reduced grey matter volume in left superior occipital gyrus, while we did not replicate associations with grey matter volume in other regions identified by Tan et al (2010). Our work illustrates the importance of independent replication in neuroimaging genetic studies of language-related candidate genes.
  • De Zubicaray, G., & Fisher, S. E. (Eds.). (2017). Genes, brain and language [Special Issue]. Brain and Language, 172.
  • De Zubicaray, G., & Fisher, S. E. (2017). Genes, Brain, and Language: A brief introduction to the Special Issue. Brain and Language, 172, 1-2. doi:10.1016/j.bandl.2017.08.003.
  • Adams, H. H. H., Hibar, D. P., Chouraki, V., Stein, J. L., Nyquist, P., Renteria, M. E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A. H., Jahanshad, N., Wittfeld, K., Van der Lee, S. J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K. A., Aribisala, B. S., Armstrong, N. J., Athanasiu, L., Axelsson, T., Beiser, A., Bernard, M., Bis, J. C., Blanken, L. M. E., Blanton, S. H., Bohlken, M. M., Boks, M. P., Bralten, J., Brickman, A. M., Carmichael, O., Chakravarty, M. M., Chauhan, G., Chen, Q., Ching, C. R. K., Cuellar-Partida, G., Den Braber, A., Doan, N. T., Ehrlich, S., Filippi, I., Ge, T., Giddaluru, S., Goldman, A. L., Gottesman, R. F., Greven, C. U., Grimm, O., Griswold, M. E., Guadalupe, T., Hass, J., Haukvik, U. K., Hilal, S., Hofer, E., Höhn, D., Holmes, A. J., Hoogman, M., Janowitz, D., Jia, T., Karbalai, N., Kasperaviciute, D., Kim, S., Klein, M., Krämer, B., Lee–, P. H., Liao, J., Liewald, D. C. M., Lopez, L. M., Luciano, M., Macare, C., Marquand, A., Matarin, M., Mather, K. A., Mattheisen, M., Mazoyer, B., McKay, D. R., McWhirter, R., Milaneschi, Y., Muetzel, R. L., Muñoz Maniega, S., Nho, K., Nugent, A. C., Olde Loohuis, L. M., Oosterlaan, J., Papmeyer, M., Pappa, I., Pirpamer, L., Pudas, S., Pütz, B., Rajan, K. B., Ramasamy, A., Richards, J. S., Risacher, S. L., Roiz-Santiañez, R., Rommelse, N., Rose, E. J., Royle, N. A., Rundek, T., Sämann, P. G., Satizabal, C. L., Schmaal, L., Schork, A. J., Shen, L., Shin, J., Shumskaya, E., Smith, A. V., Sprooten, E., Strike, L. T., Teumer, A., Thomson, R., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Vaidya, D., Van der Grond, J., Van der Meer, D., Van Donkelaar, M. M. J., Van Eijk, K. R., VanErp, T. G. M., Van Rooij, D., Walton, E., Westlye, L. T., Whelan, C. D., Windham, B. G., Winkler, A. M., Woldehawariat, G., Wolf, C., Wolfers, T., Xu, B., Yanek, L. R., Yang, J., Zijdenbos, A., Zwiers, M. P., Agartz, I., Aggarwal, N. T., Almasy, L., Ames, D., Amouyel, P., Andreassen, O. A., Arepalli, S., Assareh, A. A., Barral, S., Bastin, M. E., Becker, J. T., Becker, D. M., Bennett, D. A., Blangero, J., Van Bokhoven, H., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Brunner, H. G., Buckner, R. L., Buitelaar, J. K., Bulayeva, K. B., Cahn, W., Calhoun, V. D., Cannon, D. M., Cavalleri, G. L., Chen, C., Cheng, C.-Y., Cichon, S., Cookson, M. R., Corvin, A., Crespo-Facorro, B., Curran, J. E., Czisch, M., Dale, A. M., Davies, G. E., De Geus, E. J. C., De Jager, P. L., De Zubicaray, G. I., Delanty, N., Depondt, C., DeStefano, A., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W. C., Duggirala, R., Dyer, T. D., Erk, S., Espeseth, T., Evans, D. A., Fedko, I. O., Fernández, G., Ferrucci, L., Fisher, S. E., Fleischman, D. A., Ford, I., Foroud, T. M., Fox, P. T., Francks, C., Fukunaga, M., Gibbs, J. R., Glahn, D. C., Gollub, R. L., Göring, H. H. H., Grabe, H. J., Green, R. C., Gruber, O., Guelfi, S., Hansell, N. K., Hardy, J., Hartman, C. A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D. G., Heslenfeld, D. J., Ho, B.-C., Hoekstra, P. J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J.-J., Hulshoff Pol, H. E., Ikeda, M., Ikram, M. K., Jack Jr, C. R., Jenkinson, M., Johnson, R., Jönsson, E. G., Jukema, J. W., Kahn, R. S., Kanai, R., Kloszewska, I., Knopman, D. S., Kochunov, P., Kwok, J. B., Launer, L. J., Lawrie, S. M., Lemaître, H., Liu, X., Longo, D. L., Longstreth Jr, W. T., Lopez, O. L., Lovestone, S., Martinez, O., Martinot, J.-L., Mattay, V. S., McDonald, C., McIntosh, A. M., McMahon, F. J., McMahon, K. L., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G. W., Morris, D. W., Mosley, T. H., Mühleisen, T. W., Müller-Myhsok, B., Nalls, M. A., Nauck, M., Nichols, T. E., Niessen, W. J., Nöthen, M. M., Nyberg, L., Ohi, K., Olvera, R. L., Ophoff, R. A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B. W. J. H., Pike, G. B., Potkin, S. G., Psaty, B. M., Reppermund, S., Rietschel, M., Roffman, J. L., Romanczuk-Seiferth, N., Rotter, J. I., Ryten, M., Sacco, R. L., Sachdev, P. S., Saykin, A. J., Schmidt, R., Schofield, P. R., Sigursson, S., Simmons, A., Singleton, A., Sisodiya, S. M., Smith, C., Smoller, J. W., Soininen, H., Srikanth, V., Steen, V. M., Stott, D. J., Sussmann, J. E., Thalamuthu, A., Tiemeier, H., Toga, A. W., Traynor, B., Troncoso, J., Turner, J. A., Tzourio, C., Uitterlinden, A. G., Valdés Hernández, M. C., Van der Brug, M., Van der Lugt, A., Van der Wee, N. J. A., Van Duijn, C. M., Van Haren, N. E. M., Van 't Ent, D., Van Tol, M.-J., Vardarajan, B. N., Veltman, D. J., Vernooij, M. W., Völzke, H., Walter, H., Wardlaw, J. M., Wassink, T. H., Weale, M. E., Weinberger, D. R., Weiner, M. W., Wen, W., Westman, E., White, T., Wong, T. Y., Wright, C. B., Zielke, R. H., Zonderman, A. B., the Alzheimer's Disease Neuroimaging Initiative, EPIGEN, IMAGEN, SYS, Deary, I. J., DeCarli, C., Schmidt, H., Martin, N. G., De Craen, A. J. M., Wright, M. J., Gudnason, V., Schumann, G., Fornage, M., Franke, B., Debette, S., Medland, S. E., Ikram, M. A., & Thompson, P. M. (2016). Novel genetic loci underlying human intracranial volume identified through genome-wide association. Nature Neuroscience, 19, 1569-1582. doi:10.1038/nn.4398.

    Abstract

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson’s disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth.
  • Becker, M., Guadalupe, T., Franke, B., Hibar, D. P., Renteria, M. E., Stein, J. L., Thompson, P. M., Francks, C., Vernes, S. C., & Fisher, S. E. (2016). Early developmental gene enhancers affect subcortical volumes in the adult human brain. Human Brain Mapping, 37(5), 1788-1800. doi:10.1002/hbm.23136.

    Abstract

    Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype–phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations.
  • Carrion Castillo, A., van Bergen, E., Vino, A., van Zuijen, T., de Jong, P. F., Francks, C., & Fisher, S. E. (2016). Evaluation of results from genome-wide studies of language and reading in a novel independent dataset. Genes, Brain and Behavior, 15(6), 531-541. doi:10.1111/gbb.12299.

    Abstract

    Recent genome wide association scans (GWAS) for reading and language abilities have pin-pointed promising new candidate loci. However, the potential contributions of these loci remain to be validated. In the present study, we tested 17 of the most significantly associated single nucleotide polymorphisms (SNPs) from these GWAS studies (p < 10−6 in the original studies) in a new independent population dataset from the Netherlands: known as FIOLA (Familial Influences On Literacy Abilities). This dataset comprised 483 children from 307 nuclear families, plus 505 adults (including parents of participating children), and provided adequate statistical power to detect the effects that were previously reported. The following measures of reading and language performance were collected: word reading fluency, nonword reading fluency, phonological awareness, and rapid automatized naming. Two SNPs (rs12636438, rs7187223) were associated with performance in multivariate and univariate testing, but these did not remain significant after correction for multiple testing. Another SNP (rs482700) was only nominally associated in the multivariate test. For the rest of the SNPs we did not find supportive evidence of association. The findings may reflect differences between our study and the previous investigations in respects such as the language of testing, the exact tests used, and the recruitment criteria. Alternatively, most of the prior reported associations may have been false positives. A larger scale GWAS meta-analysis than those previously performed will likely be required to obtain robust insights into the genomic architecture underlying reading and language.
  • Chabout, J., Sarkar, A., Patel, S., Radden, T., Dunson, D., Fisher, S. E., & Jarvis, E. (2016). A Foxp2 mutation implicated in human speech deficits alters sequencing of ultrasonic vocalizations in adult male mice. Frontiers in Behavioral Neuroscience, 10: 197. doi:10.3389/fnbeh.2016.00197.

    Abstract

    Development of proficient spoken language skills is disrupted by mutations of the FOXP2 transcription factor. A heterozygous missense mutation in the KE family causes speech apraxia, involving difficulty producing words with complex learned sequences of syllables. Manipulations in songbirds have helped to elucidate the role of this gene in vocal learning, but findings in non-human mammals have been limited or inconclusive. Here we performed a systematic study of ultrasonic vocalizations (USVs) of adult male mice carrying the KE family mutation. Using novel statistical tools, we found that Foxp2 heterozygous mice did not have detectable changes in USV syllable acoustic structure, but produced shorter sequences and did not shift to more complex syntax in social contexts where wildtype animals did. Heterozygous mice also displayed a shift in the position of their rudimentary laryngeal motor cortex layer-5 neurons. Our findings indicate that although mouse USVs are mostly innate, the underlying contributions of FoxP2 to sequencing of vocalizations are conserved with humans.
  • Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E., Turner, C., Thevenon, J., Mellul, K., Sánchez-Andrade, G., Ibarra-Soria, X., Derizioti, P., Santos, R. F., Lee, S.-C., Faivre, L., Kleefstra, T., Liu, P., Hurles, M. E., DDD Study, Fisher, S. E., & Logan, D. W. (2016). BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription. The American Journal of Human Genetics, 99(2), 253-274. doi:10.1016/j.ajhg.2016.05.030.

    Abstract

    Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes
  • Estruch, S. B., Graham, S. A., Chinnappa, S. M., Deriziotis, P., & Fisher, S. E. (2016). Functional characterization of rare FOXP2 variants in neurodevelopmental disorder. Journal of Neurodevelopmental Disorders, 8: 44. doi:10.1186/s11689-016-9177-2.
  • Estruch, S. B., Graham, S. A., Deriziotis, P., & Fisher, S. E. (2016). The language-related transcription factor FOXP2 is post-translationally modified with small ubiquitin-like modifiers. Scientific Reports, 6: 20911. doi:10.1038/srep20911.

    Abstract

    Mutations affecting the transcription factor FOXP2 cause a rare form of severe speech and language disorder. Although it is clear that sufficient FOXP2 expression is crucial for normal brain development, little is known about how this transcription factor is regulated. To investigate post-translational mechanisms for FOXP2 regulation, we searched for protein interaction partners of FOXP2, and identified members of the PIAS family as novel FOXP2 interactors. PIAS proteins mediate post-translational modification of a range of target proteins with small ubiquitin-like modifiers (SUMOs). We found that FOXP2 can be modified with all three human SUMO proteins and that PIAS1 promotes this process. An aetiological FOXP2 mutation found in a family with speech and language disorder markedly reduced FOXP2 SUMOylation. We demonstrate that FOXP2 is SUMOylated at a single major site, which is conserved in all FOXP2 vertebrate orthologues and in the paralogues FOXP1 and FOXP4. Abolishing this site did not lead to detectable changes in FOXP2 subcellular localization, stability, dimerization or transcriptional repression in cellular assays, but the conservation of this site suggests a potential role for SUMOylation in regulating FOXP2 activity in vivo.

    Supplementary material

    srep20911-s1.pdf
  • Fedorenko, E., Morgan, A., Murray, E., Cardinaux, A., Mei, C., Tager-Flusberg, H., Fisher, S. E., & Kanwisher, N. (2016). A highly penetrant form of childhood apraxia of speech due to deletion of 16p11.2. European Journal of Human Genetics, 24(2), 302-306. doi:10.1038/ejhg.2015.149.

    Abstract

    Individuals with heterozygous 16p11.2 deletions reportedly suffer from a variety of difficulties with speech and language. Indeed, recent copy-number variant screens of children with childhood apraxia of speech (CAS), a specific and rare motor speech disorder, have identified three unrelated individuals with 16p11.2 deletions. However, the nature and prevalence of speech and language disorders in general, and CAS in particular, is unknown for individuals with 16p11.2 deletions. Here we took a genotype-first approach, conducting detailed and systematic characterization of speech abilities in a group of 11 unrelated children ascertained on the basis of 16p11.2 deletions. To obtain the most precise and replicable phenotyping, we included tasks that are highly diagnostic for CAS, and we tested children under the age of 18 years, an age group where CAS has been best characterized. Two individuals were largely nonverbal, preventing detailed speech analysis, whereas the remaining nine met the standard accepted diagnostic criteria for CAS. These results link 16p11.2 deletions to a highly penetrant form of CAS. Our findings underline the need for further precise characterization of speech and language profiles in larger groups of affected individuals, which will also enhance our understanding of how genetic pathways contribute to human communication disorders.
  • Fisher, S. E. (2016). A molecular genetic perspective on speech and language. In G. Hickok, & S. Small (Eds.), Neurobiology of Language (pp. 13-24). Amsterdam: Elsevier. doi:10.1016/B978-0-12-407794-2.00002-X.

    Abstract

    The rise of genomic technologies has yielded exciting new routes for studying the biological foundations of language. Researchers have begun to identify genes implicated in neurodevelopmental disorders that disrupt speech and language skills. This chapter illustrates how such work can provide powerful entry points into the critical neural pathways using FOXP2 as an example. Rare mutations of this gene cause problems with learning to sequence mouth movements during speech, accompanied by wide-ranging impairments in language production and comprehension. FOXP2 encodes a regulatory protein, a hub in a network of other genes, several of which have also been associated with language-related impairments. Versions of FOXP2 are found in similar form in many vertebrate species; indeed, studies of animals and birds suggest conserved roles in the development and plasticity of certain sets of neural circuits. Thus, the contributions of this gene to human speech and language involve modifications of evolutionarily ancient functions.
  • Franke, B., Stein, J. L., Ripke, S., Anttila, V., Hibar, D. P., Van Hulzen, K. J. E., Arias-Vasquez, A., Smoller, J. W., Nichols, T. E., Neale, M. C., McIntosh, A. M., Lee, P., McMahon, F. J., Meyer-Lindenberg, A., Mattheisen, M., Andreassen, O. A., Gruber, O., Sachdev, P. S., Roiz-Santiañez, R., Saykin, A. J., Ehrlich, S., Mather, K. A., Turner, J. A., Schwarz, E., Thalamuthu, A., Yao, Y., Ho, Y. Y. W., Martin, N. G., Wright, M. J., Guadalupe, T., Fisher, S. E., Francks, C., Schizophrenia Working Group of the Psychiatric Genomics Consortium, ENIGMA Consortium, O’Donovan, M. C., Thompson, P. M., Neale, B. M., Medland, S. E., & Sullivan, P. F. (2016). Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nature Neuroscience, 19, 420-431. doi:10.1038/nn.4228.

    Abstract

    Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders

    Supplementary material

    Franke_etal_2016_supp1.pdf
  • Gaub, S., Fisher, S. E., & Ehret, G. (2016). Ultrasonic vocalizations of adult male Foxp2-mutant mice: Behavioral contexts of arousal and emotion. Genes, Brain and Behavior, 15(2), 243-259. doi:10.1111/gbb.12274.

    Abstract

    Adult mouse ultrasonic vocalizations (USVs) occur in multiple behavioral and stimulus contexts associated with various levels of arousal, emotion, and social interaction. Here, in three experiments of increasing stimulus intensity (water; female urine; male interacting with adult female), we tested the hypothesis that USVs of adult males express the strength of arousal and emotion via different USV parameters (18 parameters analyzed). Furthermore, we analyzed two mouse lines with heterozygous Foxp2 mutations (R552H missense, S321X nonsense), known to produce severe speech and language disorders in humans. These experiments allowed us to test whether intact Foxp2 function is necessary for developing full adult USV repertoires, and whether mutations of this gene influence instinctive vocal expressions based on arousal and emotion. The results suggest that USV calling rate characterizes the arousal level, while sound pressure and spectro-temporal call complexity (overtones/harmonics, type of frequency jumps) may provide indices of levels of positive emotion. The presence of Foxp2 mutations did not qualitatively affect the USVs; all USV types that were found in wild-type animals also occurred in heterozygous mutants. However, mice with Foxp2 mutations displayed quantitative differences in USVs as compared to wild-types, and these changes were context dependent. Compared to wild-type animals, heterozygous mutants emitted mainly longer and louder USVs at higher minimum frequencies with a higher occurrence rate of overtones/harmonics and complex frequency jump types. We discuss possible hypotheses about Foxp2 influence on emotional vocal expressions, which can be investigated in future experiments using selective knockdown of Foxp2 in specific brain circuits.
  • Gialluisi, A., Visconti, A., Wilcutt, E. G., Smith, S., Pennington, B., Falchi, M., DeFries, J., Olson, R., Francks, C., & Fisher, S. E. (2016). Investigating the effects of copy number variants on reading and language performance. Journal of Neurodevelopmental Disorders, 8: 17. doi:10.1186/s11689-016-9147-8.

    Abstract

    Background Reading and language skills have overlapping genetic bases, most of which are still unknown. Part of the missing heritability may be caused by copy number variants (CNVs). Methods In a dataset of children recruited for a history of reading disability (RD, also known as dyslexia) or attention deficit hyperactivity disorder (ADHD) and their siblings, we investigated the effects of CNVs on reading and language performance. First, we called CNVs with PennCNV using signal intensity data from Illumina OmniExpress arrays (~723,000 probes). Then, we computed the correlation between measures of CNV genomic burden and the first principal component (PC) score derived from several continuous reading and language traits, both before and after adjustment for performance IQ. Finally, we screened the genome, probe-by-probe, for association with the PC scores, through two complementary analyses: we tested a binary CNV state assigned for the location of each probe (i.e., CNV+ or CNV−), and we analyzed continuous probe intensity data using FamCNV. Results No significant correlation was found between measures of CNV burden and PC scores, and no genome-wide significant associations were detected in probe-by-probe screening. Nominally significant associations were detected (p~10−2–10−3) within CNTN4 (contactin 4) and CTNNA3 (catenin alpha 3). These genes encode cell adhesion molecules with a likely role in neuronal development, and they have been previously implicated in autism and other neurodevelopmental disorders. A further, targeted assessment of candidate CNV regions revealed associations with the PC score (p~0.026–0.045) within CHRNA7 (cholinergic nicotinic receptor alpha 7), which encodes a ligand-gated ion channel and has also been implicated in neurodevelopmental conditions and language impairment. FamCNV analysis detected a region of association (p~10−2–10−4) within a frequent deletion ~6 kb downstream of ZNF737 (zinc finger protein 737, uncharacterized protein), which was also observed in the association analysis using CNV calls. Conclusions These data suggest that CNVs do not underlie a substantial proportion of variance in reading and language skills. Analysis of additional, larger datasets is warranted to further assess the potential effects that we found and to increase the power to detect CNV effects on reading and language.
  • Morgan, A., Fisher, S. E., Scheffer, I., & Hildebrand, M. (2016). FOXP2-related speech and language disorders. In R. A. Pagon, M. P. Adam, H. H. Ardinger, S. E. Wallace, A. Amemiya, L. J. Bean, T. D. Bird, C.-T. Fong, H. C. Mefford, R. J. Smith, & K. Stephens (Eds.), GeneReviews® [internet]. Seattle (WA): University of Washington, Seattle. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK368474/.
  • Li, S., Morley, M., Lu, M., Zhou, S., Stewart, K., French, C. A., Tucker, H. O., Fisher, S. E., & Morrisey, E. E. (2016). Foxp transcription factors suppress a non-pulmonary gene expression program to permit proper lung development. Developmental Biology, 416(2), 338-346. doi:10.1016/j.ydbio.2016.06.020.

    Abstract

    The inhibitory mechanisms that prevent gene expression programs from one tissue to be expressed in another are poorly understood. Foxp1/2/4 are forkhead transcription factors that repress gene expression and are individually important for endoderm development. We show that combined loss of all three Foxp1/2/4 family members in the developing anterior foregut endoderm leads to a loss of lung endoderm lineage commitment and subsequent development. Foxp1/2/4 deficient lungs express high levels of transcriptional regulators not normally expressed in the developing lung, including Pax2, Pax8, Pax9 and the Hoxa9-13 cluster. Ectopic expression of these transcriptional regulators is accompanied by decreased expression of lung restricted transcription factors including Nkx2-1, Sox2, and Sox9. Foxp1 binds to conserved forkhead DNA binding sites within the Hoxa9-13 cluster, indicating a direct repression mechanism. Thus, Foxp1/2/4 are essential for promoting lung endoderm development by repressing expression of non-pulmonary transcription factors
  • Sollis, E., Graham, S. A., Vino, A., Froehlich, H., Vreeburg, M., Dimitropoulou, D., Gilissen, C., Pfundt, R., Rappold, G., Brunner, H. G., Deriziotis, P., & Fisher, S. E. (2016). Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder. Human Molecular Genetics, 25(3), 546-557. doi:10.1093/hmg/ddv495.

    Abstract

    De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.

    Supplementary material

    ddv495supp.pdf
  • Woo, Y. J., Wang, T., Guadalupe, T., Nebel, R. A., Vino, A., Del Bene, V. A., Molholm, S., Ross, L. A., Zwiers, M. P., Fisher, S. E., Foxe, J. J., & Abrahams, B. S. (2016). A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus. PLoS One, 11(6): e0158036. doi:10.1371/journal.pone.0158036.

    Abstract

    s Metrics Comments Related Content Abstract Introduction Materials and Methods Results Discussion Supporting Information Acknowledgments Author Contributions References Reader Comments (0) Media Coverage Figures Abstract Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs) across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG), a cortical structure implicated in speech and language in independent discovery (n = 100) and validation cohorts (n = 2621). In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci.
  • Becker, M., Devanna, P., Fisher, S. E., & Vernes, S. C. (2015). A chromosomal rearrangement in a child with severe speech and language disorder separates FOXP2 from a functional enhancer. Molecular Cytogenetics, 8: 69. doi:10.1186/s13039-015-0173-0.

    Abstract

    Mutations of FOXP2 in 7q31 cause a rare disorder involving speech apraxia, accompanied by expressive and receptive language impairments. A recent report described a child with speech and language deficits, and a genomic rearrangement affecting chromosomes 7 and 11. One breakpoint mapped to 7q31 and, although outside its coding region, was hypothesised to disrupt FOXP2 expression. We identified an element 2 kb downstream of this breakpoint with epigenetic characteristics of an enhancer. We show that this element drives reporter gene expression in human cell-lines. Thus, displacement of this element by translocation may disturb gene expression, contributing to the observed language phenotype.
  • Brucato, N., Guadalupe, T., Franke, B., Fisher, S. E., & Francks, C. (2015). A schizophrenia-associated HLA locus affects thalamus volume and asymmetry. Brain, Behavior, and Immunity, 46, 311-318. doi:10.1016/j.bbi.2015.02.021.

    Abstract

    Genes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to schizophrenia, while volumetric changes of the thalamus and hippocampus have also been linked to schizophrenia. We therefore investigated whether common variants of the HLA would affect volumetric variation of the thalamus and hippocampus. We analyzed thalamus and hippocampus volumes, as measured using structural magnetic resonance imaging, in 1.265 healthy participants. These participants had also been genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. We imputed genotypes for single nucleotide polymorphisms at high density across the HLA locus, as well as HLA allotypes and HLA amino acids, by use of a reference population dataset that was specifically targeted to the HLA region. We detected a significant association of the SNP rs17194174 with thalamus volume (nominal P=0.0000017, corrected P=0.0039), as well as additional SNPs within the same region of linkage disequilibrium. This effect was largely lateralized to the left thalamus and is localized within a genomic region previously associated with schizophrenia. The associated SNPs are also clustered within a potential regulatory element, and a region of linkage disequilibrium that spans genes expressed in the thalamus, including HLA-A. Our data indicate that genetic variation within the HLA region influences the volume and asymmetry of the human thalamus. The molecular mechanisms underlying this association may relate to HLA influences on susceptibility to schizophrenia
  • Ceroni, F., Simpson, N. H., Francks, C., Baird, G., Conti-Ramsden, G., Clark, A., Bolton, P. F., Hennessy, E. R., Donnelly, P., Bentley, D. R., Martin, H., IMGSAC, SLI Consortium, WGS500 Consortium, Parr, J., Pagnamenta, A. T., Maestrini, E., Bacchelli, E., Fisher, S. E., & Newbury, D. F. (2015). Reply to Pembrey et al: ‘ZNF277 microdeletions, specific language impairment and the meiotic mismatch methylation (3M) hypothesis’. European Journal of Human Genetics, 23, 1113-1115. doi:10.1038/ejhg.2014.275.
  • Chen, J., Calhoun, V. D., Arias-Vasquez, A., Zwiers, M. P., Van Hulzen, K., Fernández, G., Fisher, S. E., Franke, B., Turner, J. A., & Liu, J. (2015). G-Protein genomic association with normal variation in gray matter density. Human Brain Mapping, 36(11), 4272-4286. doi:10.1002/hbm.22916.

    Abstract

    While detecting genetic variations underlying brain structures helps reveal mechanisms of neural disorders, high data dimensionality poses a major challenge for imaging genomic association studies. In this work, we present the application of a recently proposed approach, parallel independent component analysis with reference (pICA-R), to investigate genomic factors potentially regulating gray matter variation in a healthy population. This approach simultaneously assesses many variables for an aggregate effect and helps to elicit particular features in the data. We applied pICA-R to analyze gray matter density (GMD) images (274,131 voxels) in conjunction with single nucleotide polymorphism (SNP) data (666,019 markers) collected from 1,256 healthy individuals of the Brain Imaging Genetics (BIG) study. Guided by a genetic reference derived from the gene GNA14, pICA-R identified a significant SNP-GMD association (r = −0.16, P = 2.34 × 10−8), implying that subjects with specific genotypes have lower localized GMD. The identified components were then projected to an independent dataset from the Mind Clinical Imaging Consortium (MCIC) including 89 healthy individuals, and the obtained loadings again yielded a significant SNP-GMD association (r = −0.25, P = 0.02). The imaging component reflected GMD variations in frontal, precuneus, and cingulate regions. The SNP component was enriched in genes with neuronal functions, including synaptic plasticity, axon guidance, molecular signal transduction via PKA and CREB, highlighting the GRM1, PRKCH, GNA12, and CAMK2B genes. Collectively, our findings suggest that GNA12 and GNA14 play a key role in the genetic architecture underlying normal GMD variation in frontal and parietal regions
  • Fisher, S. E., & Vernes, S. C. (2015). Genetics and the Language Sciences. Annual Review of Linguistics, 1, 289-310. doi:10.1146/annurev-linguist-030514-125024.

    Abstract

    Theories addressing the biological basis of language must be built on an appreciation of the ways that molecular and neurobiological substrates can contribute to aspects of human cognition. Here, we lay out the principles by which a genome could potentially encode the necessary information to produce a language-ready brain. We describe what genes are; how they are regulated; and how they affect the formation, function, and plasticity of neuronal circuits. At each step, we give examples of molecules implicated in pathways that are important for speech and language. Finally, we discuss technological advances in genomics that are revealing considerable genotypic variation in the human population, from rare mutations to common polymorphisms, with the potential to relate this variation to natural variability in speech and language skills. Moving forward, an interdisciplinary approach to the language sciences, integrating genetics, neurobiology, psychology, and linguistics, will be essential for a complete understanding of our unique human capacities.
  • Fisher, S. E. (2015). Translating the genome in human neuroscience. In G. Marcus, & J. Freeman (Eds.), The future of the brain: Essays by the world's leading neuroscientists (pp. 149-159). Princeton, NJ: Princeton University Press.
  • Gascoyne, D. M., Spearman, H., Lyne, L., Puliyadi, R., Perez-Alcantara, M., Coulton, L., Fisher, S. E., Croucher, P. I., & Banham, A. H. (2015). The forkhead transcription factor FOXP2 is required for regulation of p21 WAF1/CIP1 in 143B osteosarcoma cell growth arrest. PLoS One, 10(6): e0128513. doi:10.1371/journal.pone.0128513.

    Abstract

    Mutations of the forkhead transcription factor FOXP2 gene have been implicated in inherited speech-and-language disorders, and specific Foxp2 expression patterns in neuronal populations and neuronal phenotypes arising from Foxp2 disruption have been described. However, molecular functions of FOXP2 are not completely understood. Here we report a requirement for FOXP2 in growth arrest of the osteosarcoma cell line 143B. We observed endogenous expression of this transcription factor both transiently in normally developing murine osteoblasts and constitutively in human SAOS-2 osteosarcoma cells blocked in early osteoblast development. Critically, we demonstrate that in 143B osteosarcoma cells with minimal endogenous expression, FOXP2 induced by growth arrest is required for up-regulation of p21WAF1/CIP1. Upon growth factor withdrawal, FOXP2 induction occurs rapidly and precedes p21WAF1/CIP1 activation. Additionally, FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1). Our data are consistent with a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology
  • Gingras, B., Honing, H., Peretz, I., Trainor, L. J., & Fisher, S. E. (2015). Defining the biological bases of individual differences in musicality. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 370: 20140092. doi:10.1098/rstb.2014.0092.

    Abstract

    Advances in molecular technologies make it possible to pinpoint genomic factors associated with complex human traits. For cognition and behaviour, identification of underlying genes provides new entry points for deciphering the key neurobiological pathways. In the past decade, the search for genetic correlates of musicality has gained traction. Reports have documented familial clustering for different extremes of ability, including amusia and absolute pitch (AP), with twin studies demonstrating high heritability for some music-related skills, such as pitch perception. Certain chromosomal regions have been linked to AP and musical aptitude, while individual candidate genes have been investigated in relation to aptitude and creativity. Most recently, researchers in this field started performing genome-wide association scans. Thus far, studies have been hampered by relatively small sample sizes and limitations in defining components of musicality, including an emphasis on skills that can only be assessed in trained musicians. With opportunities to administer standardized aptitude tests online, systematic large-scale assessment of musical abilities is now feasible, an important step towards high-powered genome-wide screens. Here, we offer a synthesis of existing literatures and outline concrete suggestions for the development of comprehensive operational tools for the analysis of musical phenotypes.
  • Graham, S. A., Deriziotis, P., & Fisher, S. E. (2015). Insights into the genetic foundations of human communication. Neuropsychology Review, 25(1), 3-26. doi:10.1007/s11065-014-9277-2.

    Abstract

    The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior
  • Graham, S. A., & Fisher, S. E. (2015). Understanding language from a genomic perspective. Annual Review of Genetics, 49, 131-160. doi:10.1146/annurev-genet-120213-092236.

    Abstract

    Language is a defining characteristic of the human species, but its foundations remain mysterious. Heritable disorders offer a gateway into biological underpinnings, as illustrated by the discovery that FOXP2 disruptions cause a rare form of speech and language impairment. The genetic architecture underlying language-related disorders is complex, and although some progress has been made, it has proved challenging to pinpoint additional relevant genes with confidence. Next-generation sequencing and genome-wide association studies are revolutionizing understanding of the genetic bases of other neurodevelopmental disorders, like autism and schizophrenia, and providing fundamental insights into the molecular networks crucial for typical brain development. We discuss how a similar genomic perspective, brought to the investigation of language-related phenotypes, promises to yield equally informative discoveries. Moreover, we outline how follow-up studies of genetic findings using cellular systems and animal models can help to elucidate the biological mechanisms involved in the development of brain circuits supporting language.

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  • Guadalupe, T., Zwiers, M. P., Wittfeld, K., Teumer, A., Vasquez, A. A., Hoogman, M., Hagoort, P., Fernandez, G., Buitelaar, J., van Bokhoven, H., Hegenscheid, K., Völzke, H., Franke, B., Fisher, S. E., Grabe, H. J., & Francks, C. (2015). Asymmetry within and around the human planum temporale is sexually dimorphic and influenced by genes involved in steroid hormone receptor activity. Cortex, 62, 41-55. doi:10.1016/j.cortex.2014.07.015.

    Abstract

    The genetic determinants of cerebral asymmetries are unknown. Sex differences in asymmetry of the planum temporale, that overlaps Wernicke’s classical language area, have been inconsistently reported. Meta-analysis of previous studies has suggested that publication bias established this sex difference in the literature. Using probabilistic definitions of cortical regions we screened over the cerebral cortex for sexual dimorphisms of asymmetry in 2337 healthy subjects, and found the planum temporale to show the strongest sex-linked asymmetry of all regions, which was supported by two further datasets, and also by analysis with the Freesurfer package that performs automated parcellation of cerebral cortical regions. We performed a genome-wide association scan meta-analysis of planum temporale asymmetry in a pooled sample of 3095 subjects, followed by a candidate-driven approach which measured a significant enrichment of association in genes of the ´steroid hormone receptor activity´ and 'steroid metabolic process' pathways. Variants in the genes and pathways identified may affect the role of the planum temporale in language cognition.
  • Gupta, C. N., Calhoun, V. D., Rachkonda, S., Chen, J., Patel, V., Liu, J., Segall, J., Franke, B., Zwiers, M. P., Arias-Vasquez, A., Buitelaar, J., Fisher, S. E., Fernández, G., van Erp, T. G. M., Potkin, S., Ford, J., Matalon, D., McEwen, S., Lee, H. J., Mueller, B. A., Greve, D. N., Andreassen, O., Agartz, I., Gollub, R. L., Sponheim, S. R., Ehrlich, S., Wang, L., Pearlson, G., Glahn, D. S., Sprooten, E., Mayer, A. R., Stephen, J., Jung, R. E., Canive, J., Bustillo, J., & Turner, J. A. (2015). Patterns of gray matter abnormalities in schizophrenia based on an international mega-analysis. Schizophrenia Bulletin, 41(5), 1133-1142. doi:10.1093/schbul/sbu177.

    Abstract

    Analyses of gray matter concentration (GMC) deficits in patients with schizophrenia (Sz) have identified robust changes throughout the cortex. We assessed the relationships between diagnosis, overall symptom severity, and patterns of gray matter in the largest aggregated structural imaging dataset to date. We performed both source-based morphometry (SBM) and voxel-based morphometry (VBM) analyses on GMC images from 784 Sz and 936 controls (Ct) across 23 scanning sites in Europe and the United States. After correcting for age, gender, site, and diagnosis by site interactions, SBM analyses showed 9 patterns of diagnostic differences. They comprised separate cortical, subcortical, and cerebellar regions. Seven patterns showed greater GMC in Ct than Sz, while 2 (brainstem and cerebellum) showed greater GMC for Sz. The greatest GMC deficit was in a single pattern comprising regions in the superior temporal gyrus, inferior frontal gyrus, and medial frontal cortex, which replicated over analyses of data subsets. VBM analyses identified overall cortical GMC loss and one small cluster of increased GMC in Sz, which overlapped with the SBM brainstem component. We found no significant association between the component loadings and symptom severity in either analysis. This mega-analysis confirms that the commonly found GMC loss in Sz in the anterior temporal lobe, insula, and medial frontal lobe form a single, consistent spatial pattern even in such a diverse dataset. The separation of GMC loss into robust, repeatable spatial patterns across multiple datasets paves the way for the application of these methods to identify subtle genetic and clinical cohort effects.
  • Hibar, D. P., Stein, J. L., Renteria, M. E., Arias-Vasquez, A., Desrivières, S., Jahanshad, N., Toro, R., Wittfeld, K., Abramovic, L., Andersson, M., Aribisala, B. S., Armstrong, N. J., Bernard, M., Bohlken, M. M., Boks, M. P., Bralten, J., Brown, A. A., Chakravarty, M. M., Chen, Q., Ching, C. R. K., Cuellar-Partida, G., den Braber, A., Giddaluru, S., Goldman, A. L., Grimm, O., Guadalupe, T., Hass, J., Woldehawariat, G., Holmes, A. J., Hoogman, M., Janowitz, D., Jia, T., Kim, S., Klein, M., Kraemer, B., Lee, P. H., Olde Loohuis, L. M., Luciano, M., Macare, C., Mather, K. A., Mattheisen, M., Milaneschi, Y., Nho, K., Papmeyer, M., Ramasamy, A., Risacher, S. L., Roiz-Santiañez, R., Rose, E. J., Salami, A., Sämann, P. G., Schmaal, L., Schork, A. J., Shin, J., Strike, L. T., Teumer, A., Van Donkelaar, M. M. J., Van Eijk, K. R., Walters, R. K., Westlye, L. T., Whelan, C. D., Winkler, A. M., Zwiers, M. P., Alhusaini, S., Athanasiu, L., Ehrlich, S., Hakobjan, M. M. H., Hartberg, C. B., Haukvik, U. K., Heister, A. J. G. A. M., Hoehn, D., Kasperaviciute, D., Liewald, D. C. M., Lopez, L. M., Makkinje, R. R. R., Matarin, M., Naber, M. A. M., McKay, D. R., Needham, M., Nugent, A. C., Pütz, B., Royle, N. A., Shen, L., Sprooten, E., Trabzuni, D., Van der Marel, S. S. L., Van Hulzen, K. J. E., Walton, E., Wolf, C., Almasy, L., Ames, D., Arepalli, S., Assareh, A. A., Bastin, M. E., Brodaty, H., Bulayeva, K. B., Carless, M. A., Cichon, S., Corvin, A., Curran, J. E., Czisch, M., De Zubicaray, G. I., Dillman, A., Duggirala, R., Dyer, T. D., Erk, S., Fedko, I. O., Ferrucci, L., Foroud, T. M., Fox, P. T., Fukunaga, M., Gibbs, J. R., Göring, H. H. H., Green, R. C., Guelfi, S., Hansell, N. K., Hartman, C. A., Hegenscheid, K., Heinz, A., Hernandez, D. G., Heslenfeld, D. J., Hoekstra, P. J., Holsboer, F., Homuth, G., Hottenga, J.-J., Ikeda, M., Jack, C. R., Jenkinson, M., Johnson, R., Kanai, R., Keil, M., Kent, J. W., Kochunov, P., Kwok, J. B., Lawrie, S. M., Liu, X., Longo, D. L., McMahon, K. L., Meisenzahl, E., Melle, I., Mohnke, S., Montgomery, G. W., Mostert, J. C., Mühleisen, T. W., Nalls, M. A., Nichols, T. E., Nilsson, L. G., Nöthen, M. M., Ohi, K., Olvera, R. L., Perez-Iglesias, R., Pike, G. B., Potkin, S. G., Reinvang, I., Reppermund, S., Rietschel, M., Romanczuk-Seiferth, N., Rosen, G. D., Rujescu, D., Schnell, K., Schofield, P. R., Smith, C., Steen, V. M., Sussmann, J. E., Thalamuthu, A., Toga, A. W., Traynor, B. J., Troncoso, J., Turner, J. A., Valdes Hernández, M. C., van Ent, D. ’., Van der Brug, M., Van der Wee, N. J. A., Van Tol, M.-J., Veltman, D. J., Wassink, T. H., Westman, E., Zielke, R. H., Zonderman, A. B., Ashbrook, D. G., Hager, R., Lu, L., McMahon, F. J., Morris, D. W., Williams, R. W., Brunner, H. G., Buckner, R. L., Buitelaar, J. K., Cahn, W., Calhoun, V. D., Cavalleri, G. L., Crespo-Facorro, B., Dale, A. M., Davies, G. E., Delanty, N., Depondt, C., Djurovic, S., Drevets, W. C., Espeseth, T., Gollub, R. L., Ho, B.-C., Hoffmann, W., Hosten, N., Kahn, R. S., Le Hellard, S., Meyer-Lindenberg, A., Müller-Myhsok, B., Nauck, M., Nyberg, L., Pandolfo, M., Penninx, B. W. J. H., Roffman, J. L., Sisodiya, S. M., Smoller, J. W., Van Bokhoven, H., Van Haren, N. E. M., Völzke, H., Walter, H., Weiner, M. W., Wen, W., White, T., Agartz, I., Andreassen, O. A., Blangero, J., Boomsma, D. I., Brouwer, R. M., Cannon, D. M., Cookson, M. R., De Geus, E. J. C., Deary, I. J., Donohoe, G., Fernández, G., Fisher, S. E., Francks, C., Glahn, D. C., Grabe, H. J., Gruber, O., Hardy, J., Hashimoto, R., Hulshoff Pol, H. E., Jönsson, E. G., Kloszewska, I., Lovestone, S., Mattay, V. S., Mecocci, P., McDonald, C., McIntosh, A. M., Ophoff, R. A., Paus, T., Pausova, Z., Ryten, M., Sachdev, P. S., Saykin, A. J., Simmons, A., Singleton, A., Soininen, H., Wardlaw, J. M., Weale, M. E., Weinberger, D. R., Adams, H. H. H., Launer, L. J., Seiler, S., Schmidt, R., Chauhan, G., Satizabal, C. L., Becker, J. T., Yanek, L., van der Lee, S. J., Ebling, M., Fischl, B., Longstreth, W. T., Greve, D., Schmidt, H., Nyquist, P., Vinke, L. N., Van Duijn, C. M., Xue, L., Mazoyer, B., Bis, J. C., Gudnason, V., Seshadri, S., Ikram, M. A., The Alzheimer’s Disease Neuroimaging Initiative, The CHARGE Consortium, EPIGEN, IMAGEN, SYS, Martin, N. G., Wright, M. J., Schumann, G., Franke, B., Thompson, P. M., & Medland, S. E. (2015). Common genetic variants influence human subcortical brain structures. Nature, 520, 224-229. doi:10.1038/nature14101.

    Abstract

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10-33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction

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  • Lozano, R., Vino, A., Lozano, C., Fisher, S. E., & Deriziotis, P. (2015). A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment. European Journal of Human Genetics, 23, 1702-1707. doi:10.1038/ejhg.2015.66.

    Abstract

    FOXP1 (forkhead box protein P1) is a transcription factor involved in the development of several tissues, including the brain. An emerging phenotype of patients with protein-disrupting FOXP1 variants includes global developmental delay, intellectual disability and mild to severe speech/language deficits. We report on a female child with a history of severe hypotonia, autism spectrum disorder and mild intellectual disability with severe speech/language impairment. Clinical exome sequencing identified a heterozygous de novo FOXP1 variant c.1267_1268delGT (p.V423Hfs*37). Functional analyses using cellular models show that the variant disrupts multiple aspects of FOXP1 activity, including subcellular localization and transcriptional repression properties. Our findings highlight the importance of performing functional characterization to help uncover the biological significance of variants identified by genomics approaches, thereby providing insight into pathways underlying complex neurodevelopmental disorders. Moreover, our data support the hypothesis that de novo variants represent significant causal factors in severe sporadic disorders and extend the phenotype seen in individuals with FOXP1 haploinsufficiency
  • Pettigrew, K. A., Fajutrao Valles, S. F., Moll, K., Northstone, K., Ring, S., Pennell, C., Wang, C., Leavett, R., Hayiou-Thomas, M. E., Thompson, P., Simpson, N. H., Fisher, S. E., The SLI Consortium, Whitehouse, A. J., Snowling, M. J., Newbury, D. F., & Paracchini, S. (2015). Lack of replication for the myosin-18B association with mathematical ability in independent cohorts. Genes, Brain and Behavior, 14(4), 369-376. doi:10.1111/gbb.12213.

    Abstract

    Twin studies indicate that dyscalculia (or mathematical disability) is caused partly by a genetic component, which is yet to be understood at the molecular level. Recently, a coding variant (rs133885) in the myosin-18B gene was shown to be associated with mathematical abilities with a specific effect among children with dyslexia. This association represents one of the most significant genetic associations reported to date for mathematical abilities and the only one reaching genome-wide statistical significance. We conducted a replication study in different cohorts to assess the effect of rs133885 maths-related measures. The study was conducted primarily using the Avon Longitudinal Study of Parents and Children (ALSPAC), (N = 3819). We tested additional cohorts including the York Cohort, the Specific Language Impairment Consortium (SLIC) cohort and the Raine Cohort, and stratified them for a definition of dyslexia whenever possible. We did not observe any associations between rs133885 in myosin-18B and mathematical abilities among individuals with dyslexia or in the general population. Our results suggest that the myosin-18B variant is unlikely to be a main factor contributing to mathematical abilities.
  • Simpson, N. H., Ceroni, F., Reader, R. H., Covill, L. E., Knight, J. C., the SLI Consortium, Hennessy, E. R., Bolton, P. F., Conti-Ramsden, G., O’Hare, A., Baird, G., Fisher, S. E., & Newbury, D. F. (2015). Genome-wide analysis identifies a role for common copy number variants in specific language impairment. European Journal of Human Genetics, 23, 1370-1377. doi:10.1038/ejhg.2014.296.

    Abstract

    An exploratory genome-wide copy number variant (CNV) study was performed in 127 independent cases with specific language impairment (SLI), their first-degree relatives (385 individuals) and 269 population controls. Language-impaired cases showed an increased CNV burden in terms of the average number of events (11.28 vs 10.01, empirical P=0.003), the total length of CNVs (717 vs 513 Kb, empirical P=0.0001), the average CNV size (63.75 vs 51.6 Kb, empirical P=0.0005) and the number of genes spanned (14.29 vs 10.34, empirical P=0.0007) when compared with population controls, suggesting that CNVs may contribute to SLI risk. A similar trend was observed in first-degree relatives regardless of affection status. The increased burden found in our study was not driven by large or de novo events, which have been described as causative in other neurodevelopmental disorders. Nevertheless, de novo CNVs might be important on a case-by-case basis, as indicated by identification of events affecting relevant genes, such as ACTR2 and CSNK1A1, and small events within known micro-deletion/-duplication syndrome regions, such as chr8p23.1. Pathway analysis of the genes present within the CNVs of the independent cases identified significant overrepresentation of acetylcholine binding, cyclic-nucleotide phosphodiesterase activity and MHC proteins as compared with controls. Taken together, our data suggest that the majority of the risk conferred by CNVs in SLI is via common, inherited events within a ‘common disorder–common variant’ model. Therefore the risk conferred by CNVs will depend upon the combination of events inherited (both CNVs and SNPs), the genetic background of the individual and the environmental factors.

    Supplementary material

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  • Spaeth, J. M., Hunter, C. S., Bonatakis, L., Guo, M., French, C. A., Slack, I., Hara, M., Fisher, S. E., Ferrer, J., Morrisey, E. E., Stanger, B. Z., & Stein, R. (2015). The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice. Diabetologia, 58, 1836-1844. doi:10.1007/s00125-015-3635-3.

    Abstract

    Aims/hypothesis Several forkhead box (FOX) transcription factor family members have important roles in controlling pancreatic cell fates and maintaining beta cell mass and function, including FOXA1, FOXA2 and FOXM1. In this study we have examined the importance of FOXP1, FOXP2 and FOXP4 of the FOXP subfamily in islet cell development and function. Methods Mice harbouring floxed alleles for Foxp1, Foxp2 and Foxp4 were crossed with pan-endocrine Pax6-Cre transgenic mice to generate single and compound Foxp mutant mice. Mice were monitored for changes in glucose tolerance by IPGTT, serum insulin and glucagon levels by radioimmunoassay, and endocrine cell development and proliferation by immunohistochemistry. Gene expression and glucose-stimulated hormone secretion experiments were performed with isolated islets. Results Only the triple-compound Foxp1/2/4 conditional knockout (cKO) mutant had an overt islet phenotype, manifested physiologically by hypoglycaemia and hypoglucagonaemia. This resulted from the reduction in glucagon-secreting alpha cell mass and function. The proliferation of alpha cells was profoundly reduced in Foxp1/2/4 cKO islets through the effects on mediators of replication (i.e. decreased Ccna2, Ccnb1 and Ccnd2 activators, and increased Cdkn1a inhibitor). Adult islet Foxp1/2/4 cKO beta cells secrete insulin normally while the remaining alpha cells have impaired glucagon secretion. Conclusions/interpretation Collectively, these findings reveal an important role for the FOXP1, 2, and 4 proteins in governing postnatal alpha cell expansion and function.
  • Villanueva, P., Nudel, R., Hoischen, A., Fernández, M. A., Simpson, N. H., Gilissen, C., Reader, R. H., Jara, L., Echeverry, M., Francks, C., Baird, G., Conti-Ramsden, G., O’Hare, A., Bolton, P., Hennessy, E. R., the SLI Consortium, Palomino, H., Carvajal-Carmona Veltman J.A., L., Veltman, J. A., Cazier, J.-B., De Barbieri, Z., Fisher, S. E., & Newbury, D. (2015). Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for Specific Language Impairment. PLoS Genetics, 11(3): e1004925. doi:10.1371/journal.pgen.1004925.
  • Warrier, V., Chakrabarti, B., Murphy, L., Chan, A., Craig, I., Mallya, U., Lakatošová, S., Rehnstrom, K., Peltonen, L., Wheelwright, S., Allison, C., Fisher, S. E., & Baron-Cohen, S. (2015). A pooled genome-wide association study of Asperger Syndrome. PLoS One, 10(7): e0131202. doi: 10.1371/journal.pone.0131202.

    Abstract

    Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.
  • Zhao, H., Zhou, W., Yao, Z., Wan, Y., Cao, J., Zhang, L., Zhao, J., Li, H., Zhou, R., Li, B., Wei, G., Zhang, Z., French, C. A., Dekker, J. D., Yang, Y., Fisher, S. E., Tucker, H. O., & Guo, X. (2015). Foxp1/2/4 regulate endochondral ossification as a suppresser complex. Developmental Biology, 398, 242-254. doi:10.1016/j.ydbio.2014.12.007.

    Abstract

    Osteoblast induction and differentiation in developing long bones is dynamically controlled by the opposing action of transcriptional activators and repressors. In contrast to the long list of activators that have been discovered over past decades, the network of repressors is not well-defined. Here we identify the expression of Foxp1/2/4 proteins, comprised of Forkhead-box (Fox) transcription factors of the Foxp subfamily, in both perichondrial skeletal progenitors and proliferating chondrocytes during endochondral ossification. Mice carrying loss-of-function and gain-of-function Foxp mutations had gross defects in appendicular skeleton formation. At the cellular level, over-expression of Foxp1/2/4 in chondroctyes abrogated osteoblast formation and chondrocyte hypertrophy. Conversely, single or compound deficiency of Foxp1/2/4 in skeletal progenitors or chondrocytes resulted in premature osteoblast differentiation in the perichondrium, coupled with impaired proliferation, survival, and hypertrophy of chondrocytes in the growth plate. Foxp1/2/4 and Runx2 proteins interacted in vitro and in vivo, and Foxp1/2/4 repressed Runx2 transactivation function in heterologous cells. This study establishes Foxp1/2/4 proteins as coordinators of osteogenesis and chondrocyte hypertrophy in developing long bones and suggests that a novel transcriptional repressor network involving Foxp1/2/4 may regulate Runx2 during endochondral ossification.
  • Baron-Cohen, S., Murphy, L., Chakrabarti, B., Craig, I., Mallya, U., Lakatosova, S., Rehnstrom, K., Peltonen, L., Wheelwright, S., Allison, C., Fisher, S. E., & Warrier, V. (2014). A genome wide association study of mathematical ability reveals an association at chromosome 3q29, a locus associated with autism and learning difficulties: A preliminary study. PLoS One, 9(5): e96374. doi:10.1371/journal.pone.0096374.

    Abstract

    Mathematical ability is heritable, but few studies have directly investigated its molecular genetic basis. Here we aimed to identify specific genetic contributions to variation in mathematical ability. We carried out a genome wide association scan using pooled DNA in two groups of U.K. samples, based on end of secondary/high school national academic exam achievement: high (n = 419) versus low (n = 183) mathematical ability while controlling for their verbal ability. Significant differences in allele frequencies between these groups were searched for in 906,600 SNPs using the Affymetrix GeneChip Human Mapping version 6.0 array. After meeting a threshold of p<1.5×10−5, 12 SNPs from the pooled association analysis were individually genotyped in 542 of the participants and analyzed to validate the initial associations (lowest p-value 1.14 ×10−6). In this analysis, one of the SNPs (rs789859) showed significant association after Bonferroni correction, and four (rs10873824, rs4144887, rs12130910 rs2809115) were nominally significant (lowest p-value 3.278 × 10−4). Three of the SNPs of interest are located within, or near to, known genes (FAM43A, SFT2D1, C14orf64). The SNP that showed the strongest association, rs789859, is located in a region on chromosome 3q29 that has been previously linked to learning difficulties and autism. rs789859 lies 1.3 kbp downstream of LSG1, and 700 bp upstream of FAM43A, mapping within the potential promoter/regulatory region of the latter. To our knowledge, this is only the second study to investigate the association of genetic variants with mathematical ability, and it highlights a number of interesting markers for future study.
  • Brucato, N., DeLisi, L. E., Fisher, S. E., & Francks, C. (2014). Hypomethylation of the paternally inherited LRRTM1 promoter linked to schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 165(7), 555-563. doi:10.1002/ajmg.b.32258.

    Abstract

    Epigenetic effects on psychiatric traits remain relatively under-studied, and it remains unclear what the sizes of individual epigenetic effects may be, or how they vary between different clinical populations. The gene LRRTM1 (chromosome 2p12) has previously been linked and associated with schizophrenia in a parent-of-origin manner in a set of affected siblings (LOD = 4.72), indirectly suggesting a disruption of paternal imprinting at this locus in these families. From the same set of siblings that originally showed strong linkage at this locus, we analyzed 99 individuals using 454-bisulfite sequencing, from whole blood DNA, to measure the level of DNA methylation in the promoter region of LRRTM1. We also assessed seven additional loci that would be informative to compare. Paternal identity-by-descent sharing at LRRTM1, within sibling pairs, was linked to their similarity of methylation at the gene's promoter. Reduced methylation at the promoter showed a significant association with schizophrenia. Sibling pairs concordant for schizophrenia showed more similar methylation levels at the LRRTM1 promoter than diagnostically discordant pairs. The alleles of common SNPs spanning the locus did not explain this epigenetic linkage, which can therefore be considered as largely independent of DNA sequence variation and would not be detected in standard genetic association analysis. Our data suggest that hypomethylation at the LRRTM1 promoter, particularly of the paternally inherited allele, was a risk factor for the development of schizophrenia in this set of siblings affected with familial schizophrenia, and that had previously showed linkage at this locus in an affected-sib-pair context.
  • Cai, D., Fonteijn, H. M., Guadalupe, T., Zwiers, M., Wittfeld, K., Teumer, A., Hoogman, M., Arias Vásquez, A., Yang, Y., Buitelaar, J., Fernández, G., Brunner, H. G., Van Bokhoven, H., Franke, B., Hegenscheid, K., Homuth, G., Fisher, S. E., Grabe, H. J., Francks, C., & Hagoort, P. (2014). A genome wide search for quantitative trait loci affecting the cortical surface area and thickness of Heschl's gyrus. Genes, Brain and Behavior, 13, 675-685. doi:10.1111/gbb.12157.

    Abstract

    Heschl's gyrus (HG) is a core region of the auditory cortex whose morphology is highly variable across individuals. This variability has been linked to sound perception ability in both speech and music domains. Previous studies show that variations in morphological features of HG, such as cortical surface area and thickness, are heritable. To identify genetic variants that affect HG morphology, we conducted a genome-wide association scan (GWAS) meta-analysis in 3054 healthy individuals using HG surface area and thickness as quantitative traits. None of the single nucleotide polymorphisms (SNPs) showed association P values that would survive correction for multiple testing over the genome. The most significant association was found between right HG area and SNP rs72932726 close to gene DCBLD2 (3q12.1; P=2.77x10(-7)). This SNP was also associated with other regions involved in speech processing. The SNP rs333332 within gene KALRN (3q21.2; P=2.27x10(-6)) and rs143000161 near gene COBLL1 (2q24.3; P=2.40x10(-6)) were associated with the area and thickness of left HG, respectively. Both genes are involved in the development of the nervous system. The SNP rs7062395 close to the X-linked deafness gene POU3F4 was associated with right HG thickness (Xq21.1; P=2.38x10(-6)). This is the first molecular genetic analysis of variability in HG morphology
  • Ceroni, F., Simpson, N. H., Francks, C., Baird, G., Conti-Ramsden, G., Clark, A., Bolton, P. F., Hennessy, E. R., Donnelly, P., Bentley, D. R., Martin, H., IMGSAC, SLI Consortium, WGS500 Consortium, Parr, J., Pagnamenta, A. T., Maestrini, E., Bacchelli, E., Fisher, S. E., & Newbury, D. F. (2014). Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment. European Journal of Human Genetics, 22, 1165-1171. doi:10.1038/ejhg.2014.4.

    Abstract

    Specific language impairment (SLI), an unexpected failure to develop appropriate language skills despite adequate non-verbal intelligence, is a heterogeneous multifactorial disorder with a complex genetic basis. We identified a homozygous microdeletion of 21,379 bp in the ZNF277 gene (NM_021994.2), encompassing exon 5, in an individual with severe receptive and expressive language impairment. The microdeletion was not found in the proband’s affected sister or her brother who had mild language impairment. However, it was inherited from both parents, each of whom carries a heterozygous microdeletion and has a history of language problems. The microdeletion falls within the AUTS1 locus, a region linked to autistic spectrum disorders (ASDs). Moreover, ZNF277 is adjacent to the DOCK4 and IMMP2L genes, which have been implicated in ASD. We screened for the presence of ZNF277 microdeletions in cohorts of children with SLI or ASD and panels of control subjects. ZNF277 microdeletions were at an increased allelic frequency in SLI probands (1.1%) compared with both ASD family members (0.3%) and independent controls (0.4%). We performed quantitative RT-PCR analyses of the expression of IMMP2L, DOCK4 and ZNF277 in individuals carrying either an IMMP2L_DOCK4 microdeletion or a ZNF277 microdeletion. Although ZNF277 microdeletions reduce the expression of ZNF277, they do not alter the levels of DOCK4 or IMMP2L transcripts. Conversely, IMMP2L_DOCK4 microdeletions do not affect the expression levels of ZNF277. We postulate that ZNF277 microdeletions may contribute to the risk of language impairments in a manner that is independent of the autism risk loci previously described in this region.
  • Cousijn, H., Eissing, M., Fernández, G., Fisher, S. E., Franke, B., Zwers, M., Harrison, P. J., & Arias-Vasquez, A. (2014). No effect of schizophrenia risk genes MIR137, TCF4, and ZNF804A on macroscopic brain structure. Schizophrenia Research, 159, 329-332. doi:10.1016/j.schres.2014.08.007.

    Abstract

    Single nucleotide polymorphisms (SNPs) within the MIR137, TCF4, and ZNF804A genes show genome-wide association to schizophrenia. However, the biological basis for the associations is unknown. Here, we tested the effects of these genes on brain structure in 1300 healthy adults. Using volumetry and voxel-based morphometry, neither gene-wide effects—including the combined effect of the genes—nor single SNP effects—including specific psychosis risk SNPs—were found on total brain volume, grey matter, white matter, or hippocampal volume. These results suggest that the associations between these risk genes and schizophrenia are unlikely to be mediated via effects on macroscopic brain structure.
  • Deriziotis, P., Graham, S. A., Estruch, S. B., & Fisher, S. E. (2014). Investigating protein-protein interactions in live cells using Bioluminescence Resonance Energy Transfer. Journal of visualized experiments, 87: e51438. doi:10.3791/51438.

    Abstract

    Assays based on Bioluminescence Resonance Energy Transfer (BRET) provide a sensitive and reliable means to monitor protein-protein interactions in live cells. BRET is the non-radiative transfer of energy from a ‘donor’ luciferase enzyme to an ‘acceptor’ fluorescent protein. In the most common configuration of this assay, the donor is Renilla reniformis luciferase and the acceptor is Yellow Fluorescent Protein (YFP). Because the efficiency of energy transfer is strongly distance-dependent, observation of the BRET phenomenon requires that the donor and acceptor be in close proximity. To test for an interaction between two proteins of interest in cultured mammalian cells, one protein is expressed as a fusion with luciferase and the second as a fusion with YFP. An interaction between the two proteins of interest may bring the donor and acceptor sufficiently close for energy transfer to occur. Compared to other techniques for investigating protein-protein interactions, the BRET assay is sensitive, requires little hands-on time and few reagents, and is able to detect interactions which are weak, transient, or dependent on the biochemical environment found within a live cell. It is therefore an ideal approach for confirming putative interactions suggested by yeast two-hybrid or mass spectrometry proteomics studies, and in addition it is well-suited for mapping interacting regions, assessing the effect of post-translational modifications on protein-protein interactions, and evaluating the impact of mutations identified in patient DNA.

    Supplementary material

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  • Deriziotis, P., O'Roak, B. J., Graham, S. A., Estruch, S. B., Dimitropoulou, D., Bernier, R. A., Gerdts, J., Shendure, J., Eichler, E. E., & Fisher, S. E. (2014). De novo TBR1 mutations in sporadic autism disrupt protein functions. Nature Communications, 5: 4954. doi:10.1038/ncomms5954.

    Abstract

    Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.
  • French, C. A., & Fisher, S. E. (2014). What can mice tell us about Foxp2 function? Current Opinion in Neurobiology, 28, 72-79. doi:10.1016/j.conb.2014.07.003.

    Abstract

    Disruptions of the FOXP2 gene cause a rare speech and language disorder, a discovery that has opened up novel avenues for investigating the relevant neural pathways. FOXP2 shows remarkably high conservation of sequence and neural expression in diverse vertebrates, suggesting that studies in other species are useful in elucidating its functions. Here we describe how investigations of mice that carry disruptions of Foxp2 provide insights at multiple levels: molecules, cells, circuits and behaviour. Work thus far has implicated the gene in key processes including neurite outgrowth, synaptic plasticity, sensorimotor integration and motor-skill learning.
  • Gialluisi, A., Newbury, D. F., Wilcutt, E. G., Olson, R. K., DeFries, J. C., Brandler, W. M., Pennington, B. F., Smith, S. D., Scerri, T. S., Simpson, N. H., The SLI Consortium, Luciano, M., Evans, D. M., Bates, T. C., Stein, J. F., Talcott, J. B., Monaco, A. P., Paracchini, S., Francks, C., & Fisher, S. E. (2014). Genome-wide screening for DNA variants associated with reading and language traits. Genes, Brain and Behavior, 13, 686-701. doi:10.1111/gbb.12158.

    Abstract

    Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a Genome-wide Association Scan (GWAS) meta-analysis using three richly characterised datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading- and language-related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected p≈10−7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on-going international efforts to identify genes contributing to reading and language skills.
  • Guadalupe, T., Willems, R. M., Zwiers, M., Arias Vasquez, A., Hoogman, M., Hagoort, P., Fernández, G., Buitelaar, J., Franke, B., Fisher, S. E., & Francks, C. (2014). Differences in cerebral cortical anatomy of left- and right-handers. Frontiers in Psychology, 5: 261. doi:10.3389/fpsyg.2014.00261.

    Abstract

    The left and right sides of the human brain are specialized for different kinds of information processing, and much of our cognition is lateralized to an extent towards one side or the other. Handedness is a reflection of nervous system lateralization. Roughly ten percent of people are mixed- or left-handed, and they show an elevated rate of reductions or reversals of some cerebral functional asymmetries compared to right-handers. Brain anatomical correlates of left-handedness have also been suggested. However, the relationships of left-handedness to brain structure and function remain far from clear. We carried out a comprehensive analysis of cortical surface area differences between 106 left-handed subjects and 1960 right-handed subjects, measured using an automated method of regional parcellation (FreeSurfer, Destrieux atlas). This is the largest study sample that has so far been used in relation to this issue. No individual cortical region showed an association with left-handedness that survived statistical correction for multiple testing, although there was a nominally significant association with the surface area of a previously implicated region: the left precentral sulcus. Identifying brain structural correlates of handedness may prove useful for genetic studies of cerebral asymmetries, as well as providing new avenues for the study of relations between handedness, cerebral lateralization and cognition.
  • Guadalupe, T., Zwiers, M. P., Teumer, A., Wittfeld, K., Arias Vasquez, A., Hoogman, M., Hagoort, P., Fernández, G., Buitelaar, J., Hegenscheid, K., Völzke, H., Franke, B., Fisher, S. E., Grabe, H. J., & Francks, C. (2014). Measurement and genetics of human subcortical and hippocampal asymmetries in large datasets. Human Brain Mapping, 35(7), 3277-3289. doi:10.1002/hbm.22401.

    Abstract

    Functional and anatomical asymmetries are prevalent features of the human brain, linked to gender, handedness, and cognition. However, little is known about the neurodevelopmental processes involved. In zebrafish, asymmetries arise in the diencephalon before extending within the central nervous system. We aimed to identify genes involved in the development of subtle, left-right volumetric asymmetries of human subcortical structures using large datasets. We first tested the feasibility of measuring left-right volume differences in such large-scale samples, as assessed by two automated methods of subcortical segmentation (FSL|FIRST and FreeSurfer), using data from 235 subjects who had undergone MRI twice. We tested the agreement between the first and second scan, and the agreement between the segmentation methods, for measures of bilateral volumes of six subcortical structures and the hippocampus, and their volumetric asymmetries. We also tested whether there were biases introduced by left-right differences in the regional atlases used by the methods, by analyzing left-right flipped images. While many bilateral volumes were measured well (scan-rescan r = 0.6-0.8), most asymmetries, with the exception of the caudate nucleus, showed lower repeatabilites. We meta-analyzed genome-wide association scan results for caudate nucleus asymmetry in a combined sample of 3,028 adult subjects but did not detect associations at genome-wide significance (P < 5 × 10-8). There was no enrichment of genetic association in genes involved in left-right patterning of the viscera. Our results provide important information for researchers who are currently aiming to carry out large-scale genome-wide studies of subcortical and hippocampal volumes, and their asymmetries
  • Hoogman, M., Guadalupe, T., Zwiers, M. P., Klarenbeek, P., Francks, C., & Fisher, S. E. (2014). Assessing the effects of common variation in the FOXP2 gene on human brain structure. Frontiers in Human Neuroscience, 8: 473. doi:10.3389/fnhum.2014.00473.

    Abstract

    The FOXP2 transcription factor is one of the most well-known genes to have been implicated in developmental speech and language disorders. Rare mutations disrupting the function of this gene have been described in different families and cases. In a large three-generation family carrying a missense mutation, neuroimaging studies revealed significant effects on brain structure and function, most notably in the inferior frontal gyrus, caudate nucleus and cerebellum. After the identification of rare disruptive FOXP2 variants impacting on brain structure, several reports proposed that common variants at this locus may also have detectable effects on the brain, extending beyond disorder into normal phenotypic variation. These neuroimaging genetics studies used groups of between 14 and 96 participants. The current study assessed effects of common FOXP2 variants on neuroanatomy using voxel-based morphometry and volumetric techniques in a sample of >1300 people from the general population. In a first targeted stage we analyzed single nucleotide polymorphisms (SNPs) claimed to have effects in prior smaller studies (rs2253478, rs12533005, rs2396753, rs6980093, rs7784315, rs17137124, rs10230558, rs7782412, rs1456031), beginning with regions proposed in the relevant papers, then assessing impact across the entire brain. In the second gene-wide stage, we tested all common FOXP2 variation, focusing on volumetry of those regions most strongly implicated from analyses of rare disruptive mutations. Despite using a sample that is more than ten times that used for prior studies of common FOXP2 variation, we found no evidence for effects of SNPs on variability in neuroanatomy in the general population. Thus, the impact of this gene on brain structure may be largely limited to extreme cases of rare disruptive alleles. Alternatively, effects of common variants at this gene exist but are too subtle to be detected with standard volumetric techniques
  • Nudel, R., Simpson, N. H., Baird, G., O’Hare, A., Conti-Ramsden, G., Bolton, P. F., Hennessy, E. R., SLI Consortium, Monaco, A. P., Fairfax, B. P., Knight, J. C., Winney, B., Fisher, S. E., & Newbury, D. F. (2014). Associations of HLA alleles with specific language impairment. Journal of Neurodevelopmental Disorders, 6: 1. doi:10.1186/1866-1955-6-1.

    Abstract

    Background Human leukocyte antigen (HLA) loci have been implicated in several neurodevelopmental disorders in which language is affected. However, to date, no studies have investigated the possible involvement of HLA loci in specific language impairment (SLI), a disorder that is defined primarily upon unexpected language impairment. We report association analyses of single-nucleotide polymorphisms (SNPs) and HLA types in a cohort of individuals affected by language impairment. Methods We perform quantitative association analyses of three linguistic measures and case-control association analyses using both SNP data and imputed HLA types. Results Quantitative association analyses of imputed HLA types suggested a role for the HLA-A locus in susceptibility to SLI. HLA-A A1 was associated with a measure of short-term memory (P = 0.004) and A3 with expressive language ability (P = 0.006). Parent-of-origin effects were found between HLA-B B8 and HLA-DQA1*0501 and receptive language. These alleles have a negative correlation with receptive language ability when inherited from the mother (P = 0.021, P = 0.034, respectively) but are positively correlated with the same trait when paternally inherited (P = 0.013, P = 0.029, respectively). Finally, case control analyses using imputed HLA types indicated that the DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls (P = 0.004, relative risk = 2.575), as has been reported for individuals with attention deficit hyperactivity disorder (ADHD). Conclusion These preliminary data provide an intriguing link to those described by previous studies of other neurodevelopmental disorders and suggest a possible role for HLA loci in language disorders.

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