Publications

Abstract

Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis-regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.

Abstract

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10−6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Abstract

The human cerebral hemispheres show a left–right asymmetrical torque pattern, which has been claimed to be absent in chimpanzees. The functional significance and developmental mechanisms are unknown. Here, we carried out the largest-ever analysis of global brain shape asymmetry in magnetic resonance imaging data. Three population datasets were used, UK Biobank (N = 39 678), Human Connectome Project (N = 1113), and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Both skews were associated independently with handedness, and various regional gray and white matter metrics oppositely in the two hemispheres, as well as other variables related to cognitive functions, sociodemographic factors, and physical and mental health. The two skews showed single nucleotide polymorphisms-based heritabilities of 4–13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in genome-wide association studies for either skew. There was evidence for a significant genetic correlation between horizontal brain skew and autism, which requires future replication. These results provide the first large-scale description of population-average brain skews and their inter-individual variations, their replicable associations with handedness, and insights into biological and other factors which associate with human brain asymmetry.

Abstract

Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here we performed the largest-ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.
Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modelling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.
Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t=2.1, P=0.04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t=2.7, P=0.01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing.
Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely under-powered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Abstract

Autism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing versus empathizing cognitive styles, with resemblances to male versus female average sex differences. Left-right asymmetry of the brain is an important aspect of its organization that shows average differences between the sexes, and can be altered in both ASD and schizophrenia. Here we mapped multivariate associations of polygenic risk scores for ASD and schizophrenia with asymmetries of regional cerebral cortical surface area, thickness and subcortical volume measures in 32,256 participants from the UK Biobank. Polygenic risks for the two disorders were positively correlated (r=0.08, p=7.13×10-50), and both were higher in females compared to males, consistent with biased participation against higher-risk males. Each polygenic risk score was associated with multivariate brain asymmetry after adjusting for sex, ASD r=0.03, p=2.17×10-9, schizophrenia r=0.04, p=2.61×10-11, but the multivariate patterns were mostly distinct for the two polygenic risks, and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both polygenic risks were associated with asymmetries of regions important for language and executive functions, consistent with behavioural associations that arose in phenome-wide association analysis. Overall, the results indicate that distinct patterns of subtly altered brain asymmetry may be functionally relevant manifestations of polygenic risks for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies.

Abstract

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7—mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

Abstract

Left–right hemispheric asymmetry is an important aspect of healthy brain organization for many functions including language, and it can be altered in cognitive and psychiatric disorders. No mechanism has yet been identified for establishing the human brain’s left–right axis. We performed multivariate genome-wide association scanning of cortical regional surface area and thickness asymmetries, and subcortical volume asymmetries, using data from 32,256 participants from the UK Biobank. There were 21 significant loci associated with different aspects of brain asymmetry, with functional enrichment involving microtubule-related genes and embryonic brain expression. These findings are consistent with a known role of the cytoskeleton in left–right axis determination in other organs of invertebrates and frogs. Genetic variants associated with brain asymmetry overlapped with those associated with autism, educational attainment and schizophrenia. Comparably large datasets will likely be required in future studies, to replicate and further clarify the associations of microtubule-related genes with variation in brain asymmetry, behavioural and psychiatric traits.

Abstract

To understand the origins of interhemispheric differences and commonalities/coupling in human brain wiring, it is crucial to determine how homologous interregional connectivities of the left and right hemispheres are genetically determined and related. To address this, in the present study, we analyzed human twin and pedigree samples with high-quality diffusion magnetic resonance imaging tractography and estimated the heritability and genetic correlation of homologous left and right white matter (WM) connections. The results showed that the heritability of WM connectivity was similar and coupled between the 2 hemispheres and that the degree of overlap in genetic factors underlying homologous WM connectivity (i.e., interhemispheric genetic correlation) varied substantially across the human brain: from complete overlap to complete nonoverlap. Particularly, the heritability was significantly stronger and the chance of interhemispheric complete overlap in genetic factors was higher in subcortical WM connections than in cortical WM connections. In addition, the heritability and interhemispheric genetic correlations were stronger for long-range connections than for short-range connections. These findings highlight the determinants of the genetics underlying WM connectivity and its interhemispheric relationships, and provide insight into genetic basis of WM connectivity asymmetries in both healthy and disease states.

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.

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.

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.

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

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.

Abstract

Pinpointing genes involved in non-right-handedness has the potential to clarify developmental contributions to human brain lateralization. Major-gene models have been considered for human handedness which allow for phenocopy and reduced penetrance, i.e. an imperfect correspondence between genotype and phenotype. However, a recent genome-wide association scan did not detect any common polymorphisms with substantial genetic effects. Previous linkage studies in families have also not yielded significant findings. Genetic heterogeneity and/or polygenicity are therefore indicated, but it remains possible that relatively rare, or even unique, major-genetic effects may be detectable in certain extended families with many non-right-handed members. Here we applied whole exome sequencing to 17 members from a single, large consanguineous family from Pakistan. Multipoint linkage analysis across all autosomes did not yield clear candidate genomic regions for involvement in the trait and single-point analysis of exomic variation did not yield clear candidate mutations/genes. Any genetic contribution to handedness in this unusual family is therefore likely to have a complex etiology, as at the population level.

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.

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

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.

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.

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.

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

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

Abstract

Specific language impairment (SLI) is a neurodevelopmental disorder that affects
linguistic abilities when development is otherwise normal. We report the results of a genomewide association study of SLI which included parent-of-origin effects and child genotype effects and used 278 families of language-impaired children. The child genotype effects analysis did not identify significant associations. We found genome-wide significant paternal
parent-of-origin effects on chromosome 14q12 (P=3.74×10-8) and suggestive maternal parent-of-origin-effects on chromosome 5p13 (P=1.16×10-7). A subsequent targeted association of six single-nucleotide-polymorphisms (SNPs) on chromosome 5 in 313 language-impaired individuals from the ALSPAC cohort replicated the maternal effects,
albeit in the opposite direction (P=0.001); as fathers’ genotypes were not available in the ALSPAC study, the replication analysis did not include paternal parent-of-origin effects. The paternally-associated SNP on chromosome 14 yields a non-synonymous coding change within the NOP9 gene. This gene encodes an RNA-binding protein that has been reported to be significantly dysregulated in individuals with schizophrenia. The region of maternal
association on chromosome 5 falls between the PTGER4 and DAB2 genes, in a region
previously implicated in autism and ADHD. The top SNP in this association locus is a
potential expression QTL of ARHGEF19 (also called WGEF) on chromosome 1. Members of this protein family have been implicated in intellectual disability. In sum, this study implicates parent-of-origin effects in language impairment, and adds an interesting new dimension to the emerging picture of shared genetic etiology across various neurodevelopmental disorders.

Abstract

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way

Abstract

Neuregulin 1 (NRG1) and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) have been extensively studied in schizophrenia susceptibility because of their pivotal role in key neurodevelopmental processes. One of the reasons for the inconsistencies in results could be the fact that the phenotype investigated has mostly the diagnosis of schizophrenia per se, which is widely heterogeneous, both clinically and biologically. In the present study we tested, in a large cohort of 461 schizophrenia patients recruited in Scotland, whether several SNPs in NRG1 and/or ErbB4 are associated with schizophrenia symptom dimensions as evaluated by the Positive and Negative Syndrome Scale (PANSS). We then followed up nominally significant results in a second cohort of 439 schizophrenia subjects recruited in Germany. Using linear regression, we observed two different groups of polymorphisms in NRG1 gene: one showing a nominal association with higher scores of the PANSS positive dimension and the other one with higher scores of the PANSS negative dimension. Regarding ErbB4, a small cluster located in the 5' end of the gene was detected, showing nominal association mainly with negative, general and total dimensions of the PANSS. These findings suggest that some regions of NRG1 and ErbB4 are functionally involved in biological processes that underlie some of the phenotypic manifestations of schizophrenia. Because of the lack of significant association after correction for multiple testing, our analyses should be considered as exploratory and hypothesis generating for future studies.

Abstract

Left-handers are often excluded from study cohorts in neuroscience and neurogenetics in order to reduce variance in the data. However, recent investigations have shown that the inclusion or targeted recruitment of left-handers can be informative in studies on a range of topics, such as cerebral lateralization and the genetic underpinning of asymmetrical brain development. Left-handed individuals represent a substantial portion of the human population and therefore left-handedness falls within the normal range of human diversity; thus, it is important to account for this variation in our understanding of brain functioning. We call for neuroscientists and neurogeneticists to recognize the potential of studying this often-discarded group of research subjects.

Abstract

While most people prefer to use their right hand to brush their teeth, throw a ball, or hold a tennis racket, left-handers prefer to use their left hand. This is the case for around 10 per cent of all people. There was a time (not so long ago) when left-handers were stigmatized in Western (and other) communities: it was considered a bad sign if you were left-handed, and left-handed children were often forced to write with their right hand. This is nonsensical: there is nothing wrong with being left-handed, and trying to write with the non-preferred hand is frustrating for almost everybody. As a matter of fact, science can learn from left-handers, and in this paper, we discuss how this may be the case. We review why some people are left-handed and others are not, how left-handers' brains differ from right-handers’, and why scientists study left-handedness in the first place