Publications

Abstract

Previous studies have suggested that altered asymmetry of the planum temporale (PT) is associated with neurodevelopmental disorders, including dyslexia, schizophrenia, and autism. Shared genetic factors have been suggested to link PT asymmetry to these disorders. In a dataset of unrelated subjects from the general population (UK Biobank, N= 18,057), we found that PT volume asymmetry had a significant heritability of roughly 14%. In genome-wide association analysis, two loci were significantly associated with PT asymmetry, including a coding polymorphism within the gene ITIH5 that is predicted to affect the protein’s function and to be deleterious (rs41298373, P=2.01×10−15), and a locus that affects the expression of the genes BOK and DTYMK (rs7420166, P=7.54×10-10). DTYMK showed left-right asymmetry of mRNA expression in post mortem PT tissue. Cortex-wide mapping of these SNP effects revealed influences on asymmetry that went somewhat beyond the PT. Using publicly available genome-wide association statistics from large-scale studies, we saw no significant genetic correlations of PT asymmetry with autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, educational attainment or intelligence. Of the top two individual loci associated with PT asymmetry, rs41298373 showed a tentative association with intelligence (unadjusted P=0.025), while the locus at BOK/DTYMK showed tentative association with educational attainment (unadjusted Ps<0.05). These findings provide novel insights into the genetic contributions to human brain asymmetry, but do not support a substantial polygenic association of PT asymmetry with cognitive variation and mental disorders, as far as can be discerned with current sample sizes.

Abstract

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Abstract

A pivotal question in modern neuroscience is which genes regulate brain circuits that underlie cognitive functions. However, the field is still in its infancy. Here we report an integrated investigation of the high-level language network (i.e., sentence processing network) in the human cerebral cortex, combining regional gene expression profiles, task fMRI, large-scale neuroimaging meta-analysis, and resting-state functional network approaches. We revealed reliable gene expression-functional network correlations using three different network definition strategies, and identified a consensus set of genes related to connectivity within the sentence-processing network. The genes involved showed enrichment for neural development and actin-related functions, as well as association signals with autism, which can involve disrupted language functioning. Our findings help elucidate the molecular basis of the brain’s infrastructure for language. The integrative approach described here will be useful to study other complex cognitive traits.

Abstract

Objective

Lateralized dysfunction has been suggested in Obsessive-Compulsive Disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of structural brain asymmetry. Here we carried out by far the largest study of brain structural asymmetry in OCD.
Method

We studied a collection of 16 pediatric datasets (501 OCD patients and 439 healthy controls), as well as 30 adult datasets (1777 patients and 1654 controls) from the OCD Working Group within the ENIGMA (Enhancing Neuro-Imaging Genetics through Meta-Analysis) consortium. Asymmetries of the volumes of subcortical structures, and of regional cortical thickness and surface area measures, were assessed based on T1-weighted MRI scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in OCD patients. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.
Results

In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen’s d = 0.19) and the pallidum (less leftward; d = -0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, and/or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.
Conclusions

The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.

Abstract

Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD). However, most people with SI do not have PCD, and the etiology of their condition remains poorly studied. We sequenced the genomes of 15 people with SI, of which six had PCD, as well as 15 controls. Subjects with non-PCD SI in this sample had an elevated rate of left-handedness (five out of nine), which suggested possible developmental mechanisms linking brain and body laterality. The six SI subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SI cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SI cases. One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 (also known as WDR16). Both of these genes have previously been linked to SI without PCD. However, five of the nine non-PCD SI cases, including three of the left-handers in this dataset, had no obvious monogenic basis for their condition. Environmental influences, or possible random effects in early development, must be considered.

Abstract

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

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.

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.

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.

Abstract

Hand preference is a conspicuous variation in human behaviour, with a worldwide proportion of around 90% of people preferring to use the right hand for many tasks, and 10% the left hand. We used the large cohort of the UK biobank (~500,000 participants) to study possible relations between early life factors and adult hand preference. The probability of being left-handed was affected by the year and location of birth, likely due to cultural effects. In addition, hand preference was affected by birthweight, being part of a multiple birth, season of birth, breastfeeding, and sex, with each effect remaining significant after accounting for all others. Analysis of genome-wide genotype data showed that left-handedness was very weakly heritable, but shared no genetic basis with birthweight. Although on average left-handers and right-handers differed for a number of early life factors, all together these factors had only a minimal predictive value for individual hand preference.

Abstract

Objective:

Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects.
Methods:

The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen’s d=0.1.
Results:

The largest effect size (Cohen’s d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset.
Conclusions:

Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

Abstract

Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N = 331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence supporting any of the previously suggested variants or genes, nor that genes involved in visceral laterality have a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Our analysis did produce a small number of novel, significant associations, including one implicating the microtubule-associated gene MAP2 in handedness.

Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

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.

Abstract

Population-based linkage analysis is a new method for analysing genomewide single nucleotide polymorphism (SNP) genotype data in case-control samples, which does not assume a common disease, common variant model. The genome is scanned for extended segments that show increased identity-by-descent sharing within case-case pairs, relative to case-control or control-control pairs. The method is robust to allelic heterogeneity and is suited to mapping genes which contain multiple, rare susceptibility variants of relatively high penetrance. We analysed genomewide SNP datasets for two schizophrenia case-control cohorts, collected in Aberdeen (461 cases, 459 controls) and Munich (429 cases, 428 controls). Population-based linkage testing must be performed within homogeneous samples and it was therefore necessary to analyse the cohorts separately. Each cohort was first subjected to several procedures to improve genetic homogeneity, including identity-by-state outlier detection and multidimensional scaling analysis. When testing only cases who reported a positive family history of major psychiatric disease, consistent with a model of strongly penetrant susceptibility alleles, we saw a distinct peak on chromosome 19q in both cohorts that appeared in meta-analysis (P=0.000016) to surpass the traditional level for genomewide significance for complex trait linkage. The linkage signal was also present in a third case-control sample for familial bipolar disorder, such that meta-analysing all three datasets together yielded a linkage P=0.0000026. A model of rare but highly penetrant disease alleles may be more applicable to some instances of major psychiatric diseases than the common disease common variant model, and we therefore suggest that other genome scan datasets are analysed with this new, complementary method.

Abstract

The Abelson helper integration site 1 (AHI1) gene locus on chromosome 6q23 is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. Here, we present results of a replication study of AHI1 locus markers, previously implicated in schizophrenia, in a large European sample (in total 3907 affected and 7429 controls). Furthermore, we perform a meta-analysis of the implicated markers in 4496 affected and 18,920 controls. Both the replication study of new samples and the meta-analysis show evidence for significant overrepresentation of all tested alleles in patients compared with controls (meta-analysis; P = 8.2 x 10(-5)-1.7 x 10(-3), common OR = 1.09-1.11). The region contains two genes, AHI1 and C6orf217, and both genes-as well as the neighbouring phosphodiesterase 7B (PDE7B)-may be considered candidates for involvement in the genetic aetiology of schizophrenia.

Abstract

Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

Abstract

Major depressive disorder (MDD) is a highly prevalent disorder with substantial heritability. Heritability has been shown to be substantial and higher in the variant of MDD characterized by recurrent episodes of depression. Genetic studies have thus far failed to identify clear and consistent evidence of genetic risk factors for MDD. We conducted a genome-wide association study (GWAS) in two independent datasets. The first GWAS was performed on 1022 recurrent MDD patients and 1000 controls genotyped on the Illumina 550 platform. The second was conducted on 492 recurrent MDD patients and 1052 controls selected from a population-based collection, genotyped on the Affymetrix 5.0 platform. Neither GWAS identified any SNP that achieved GWAS significance. We obtained imputed genotypes at the Illumina loci for the individuals genotyped on the Affymetrix platform, and performed a meta-analysis of the two GWASs for this common set of approximately half a million SNPs. The meta-analysis did not yield genome-wide significant results either. The results from our study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in our datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays. Meta-analysis of larger datasets is warranted to identify SNPs with smaller effects or with rarer allele frequencies that contribute to the risk of MDD.