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Cortical asymmetry is a ubiquitous feature of brain organization that is altered in neurodevelopmental disorders and aging. Achieving consensus on cortical asymmetries in humans is necessary to uncover the genetic-developmental mechanisms that shape them and factors moderating cortical lateralization. Here, we delineate population-level asymmetry in cortical thickness and surface area vertex-wise in 7 datasets and chart asymmetry trajectories across life (4-89 years; observations = 3937; 70% longitudinal). We reveal asymmetry interrelationships, heritability, and test associations in UK Biobank (N=∼37,500). Cortical asymmetry was robust across datasets. Whereas areal asymmetry is predominantly stable across life, thickness asymmetry grows in development and declines in aging. Areal asymmetry correlates in specific regions, whereas thickness asymmetry is globally interrelated across cortex and suggests high directional variability in global thickness lateralization. Areal asymmetry is moderately heritable (max h2SNP ∼19%), and phenotypic correlations are reflected by high genetic correlations, whereas heritability of thickness asymmetry is low. Finally, we detected an asymmetry association with cognition and confirm recently-reported handedness links. Results suggest areal asymmetry is developmentally stable and arises in early life, whereas developmental changes in thickness asymmetry may lead to directional variability of global thickness lateralization. Our results bear enough reproducibility to serve as a standard for future brain asymmetry studies.

Handedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in eurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or brain asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) or microtubule-associated proteins. Here we examined whether left-handedness is also influenced by rare coding variants (frequencies ≤ 1%), using exome data from 38,043 left-handed and 313,271 right-handed individuals (UK Biobank). The beta-tubulin gene TUBB4B showed exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers (0.076%) than right-handers (0.028%). The TUBB4B variants were mostly heterozygous missense changes, but included two frameshifts found only in left-handers. Other TUBB4B variants have been linked to sensorineural and/or ciliopathic disorders, but not the variants found here. Among genes previously implicated in autism or schizophrenia by exome screening, DSCAM and FOXP1 showed evidence for rare coding variant association with left-handedness. The exome-wide heritability of left-handedness due to rare coding variants was 0.91%. This study revealed a role for rare, protein-altering variants in left-handedness, providing further evidence for the involvement of microtubules and disorder-relevant genes.

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10–2, threshold = 2.5 × 10–2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10–2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10–4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations., Translational Psychiatry, 12 (1), ISSN:2158-3188

Published August 23, 2022 The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 1028) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits. We thank all the children, twins, families, and participants who took part and are taking part in the 22 cohorts whose data contributed to these GWAS meta-analyses; the staff working on the different cohorts, including volunteers, study coordinators, interviewers, teachers, nurses, research scientists, general practitioners, midwives, psychologists, psychometrists, computer and laboratory technicians, and colleagues who assisted in the quality control and preparation of the imputed GWAS data; and the pharmacies and hospitals that were involved. B.M., B.M.-M., B.S.P., C.F., E.E., E.V., G.A., M.v.D., and S.E.F. are supported by the Max Planck Society. A.G. and T.F.M.A. were supported by the Munich Cluster for Systems Neurology (SyNergy), and A.G. was supported by Fondazione Umberto Veronesi. A.T.M. is supported by National Health and Medical Research Council of Australia (NHMRC) Grants 1105008 and 1195955 and Centre of Research Excellence Grant 1116976. A.J.O.W. is supported by NHMRC Grant 1173896. B.S.P. is supported by Simons Foundation Autism Research Initiative Grant 514787. C.Y.S. works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/3). D.I.B. acknowledges Royal Netherlands Academy of Science Professor Award PAH/6635. E.E. is supported by NIH Grant R01DC016977. E.G.W. and J.R.G. are supported by National Institute of Child Health and Human Development (NICHD) Grant P50 HD 27802. F.R. is supported by Agence Nationale de la Recherche Grants ANR-06-NEURO-019-01, ANR-17-EURE-0017 IEC, ANR-10-IDEX-0001-02 PSL, and ANR-11-BSV4-014-01 and European Commission Grant LSHM-CT-2005-018696. H.T. is supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) Grant VICI 016.VICI.170.200. J.C.D. was supported by NICHD Grant P50 HD 27802. J.J.M., J.B.To., and T.K. were supported by NIH Grant R01 DC014489. K.M.P. was supported by the Hospital for Sick Children Research Training Program (Restracomp). K.R. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (213514/Z/18/Z). M.J.S. is supported by Wellcome Trust Grant WT082032MA. S.P. and F.A. are supported by Royal Society Grants UF150663 and RGF\EA\180141. T.B. is supported by Institut Pasteur, the Bettencourt-Schueller Foundation, and Université de Paris. The Adolescent Brain Cognitive Development Study is supported by the NIH and additional federal partners (NIH Grants U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147). The Aston Cohort was supported by funding from European Union (EU) Horizon 2020 Programme 641652 and Waterloo Foundation Grant 797/17290. The St. Andrews Bioinformatics Unit is funded by Wellcome Trust Grants 105621/Z/14/Z and 204821/Z/16/Z. ALSPAC is supported by UK Medical Research Council and Wellcome Grant 217065/Z/19/Z and the University of Bristol. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Basque Center on Cognition, Brain and Language (BCBL) cohort was supported by the Basque Government through the Basic Excellence Research Centre program and the Agencia Estatal de Investigación through BCBL Severo Ochoa excellence accreditation. The Brisbane Adolescent Twin Sample was supported by Australian Research Council Grants A7960034, A79906588, A79801419, DP0212016, and DP0343921, with genotyping funded by the NHMRC Grant 389891. The Colorado Learning Disabilities Research Center cohort was supported by NICHD Grant P50 HD 27802. The Early Language in Victoria Study was supported by NHMRC Grant 436958. The Familial Influences on Literacy Abilities cohort is supported by the University of Amsterdam, the Max Planck Institue Nijmegen, and NWO Grants Rubicon 446-12-005 and VENI 451-15-017. The GRaD study was funded by the Manton Foundation, NIH Grants P50-HD027802 and K99-HD094902, and the Lambert Family. NeuroDys was funded by an EU Sixth Framework Program grant to the NeuroDys Consortium, Swiss National Science Foundation Grant 32-108130, and Austrian Science Fund Grant 18351-B02. The Netherlands Twin Register is funded by NWO Grants 480-04-004, 481-08-011, 056-32-010, 024.001.003, 480-15-001/674, 184.021.007, 184.033.111, and 56-464-14192; ZonMW Grants 911-09-032 and 912-10-020; the Amsterdam Public Health and Amsterdam Reproduction and Development Research Institutes; European Science Council Grant ERC Advanced 230374; EU Seventh Framework Program (FP7) Grant FP7/2007-2013: 602768; National Institute of Mental Health (NIMH) Grants U24 MH068457-06, R01 MH58799-03, and 1RC2 MH089995; and the Avera Institute for Human Genetics. The Pediatric Imaging, Neurocognition, and Genetics cohort is funded by NIH Grant RC2DA029475, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver NICHD. The Philadelphia Neurodevelopmental Cohort is funded by NIH Grants RC2MH089983 and RC2MH089924, an institutional development award to the Center for Applied Genomics from The Children’s Hospital of Philadelphia, and a donation from Adele and Daniel Kubert and thanks the NIH data repository. The Raine study was supported by long-term funding from NHMRC Grants 572613, 403981, and 1059711 and Canadian Institutes of Health Research (CIHR) Grant MOP-82893. Funding was also provided by the University of Western Australia, Curtin University, the Women and Infants Research Foundation, the Telethon Kids Institute, Edith Cowan University, Murdoch University, the University of Notre Dame Australia, and the Raine Medical Research Foundation. The Raine study analyses were supported by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. The Saguenay Youth Study is supported by the CIHR, the Heart and Stroke Foundation of Quebec, and the Canadian Foundation for Innovation. The SLI Consortium was funded by Wellcome Trust Grant 076566 and UK Medical Research Council Grant G1000569. The Twins Early Development Study is supported by UK Medical Research Council Grants MR/V012878/1 and MR/M021475/1, NIH Grant AG046938, and the EU FP7 grant FP7/2007-2013/: 602768. Toronto was supported by CIHR Grant MOP-133440. UK Dyslexia was supported by Wellcome Trust Grants 076566/Z/05/Z and 075491/Z/04, Waterloo Foundation Grant 797–1720, EU Grant 018696, and Royal Society Grant UF100463. The York cohort was funded by Wellcome Trust Grant 082036/B/07/Z. We acknowledge iPSYCH for sharing their summary statistics. The iPSYCH team was supported by Lundbeck Foundation Grants R102-A9118, R155-2014-1724, and R248-2017-2003; NIMH Grant 1U01MH109514-01; and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, Aarhus University, Denmark.

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Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

Lateralization is a fundamental characteristic of many behaviors and the organization of the brain, and atypical lateralization has been suggested to be linked to various brain-related disorders such as autism and schizophrenia. Right-handedness is one of the most prominent markers of human behavioural lateralization, yet its neurobiological basis remains to be determined. Here, we present a large-scale analysis of handedness, as measured by self-reported direction of hand preference, and its variability related to brain structural and functional organization in the UK Biobank (N = 36,024). A multivariate machine learning approach with multi-modalities of brain imaging data was adopted, to reveal how well brain imaging features could predict individual's handedness (i.e., right-handedness vs. non-right-handedness) and further identify the top brain signatures that contributed to the prediction. Overall, the results showed a good prediction performance, with an area under the receiver operating characteristic curve (AUROC) score of up to 0.72, driven largely by resting-state functional measures. Virtual lesion analysis and large-scale decoding analysis suggested that the brain networks with the highest importance in the prediction showed functional relevance to hand movement and several higher-level cognitive functions including language, arithmetic, and social interaction. Genetic analyses of contributions of common DNA polymorphisms to the imaging-derived handedness prediction score showed a significant heritability (h2=7.55%, p

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.

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.

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Dianne Newbury is an MRC Career Development Fellow and a Junior Research Fellow at St John’s College, University of Oxford. The work of the Newbury lab is funded by the Medical Research Council [G1000569/1 and MR/J003719/1]. Ron Nudel is funded by a University of Oxford Nuffield Department of Medicine Prize Studentship. The genotyping of samples was funded by the Max Planck Society. Silvia Paracchini is a Royal Society University Research Fellow. The analyses of the ALSPAC cohort were supported by a grant from the Medical Research Council [G0800523/86473]. The collection of the SLIC samples was supported by the Wellcome Trust (060774 and 076566). Patrick Bolton is supported by a National Institute of Health Research (UK) Senior Investigator award and the Biomedical Research Centre in Mental Health at the South London & Maudsley NHS Trust Hospital, London. The work of the Wellcome Trust Centre in Oxford is supported by the Wellcome Trust [090532/Z/09/Z]. Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. We report the results of a genome-wide 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. Publisher PDF

Contains fulltext : 167382.pdf (Publisher’s version ) (Closed access) 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. Hum Brain Mapp 37:1788-1800, 2016. (c) 2016 Wiley Periodicals, Inc. 13 p.

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. We could not replicate the association of the myosin-18B gene with mathematical ability.

In a recent paper,1 we described a homozygous exonic microdeletion in ZNF277 in a girl with specific language impairment (SLI). This microdeletion was also identified in the heterozygous form in eight families of the SLI Consortium (SLIC) cohort and four families with ASD cases from the IMGSAC Cohort. We observed an increased allelic frequency of ZNF277 microdeletions in SLI probands (1.1%) compared with both ASD family members (0.3%) and unrelated controls (0.4%), suggesting that these microdeletions might be a risk factor for SLI. However, as the ZNF277 microdeletions showed incomplete segregation with the SLI phenotype, as they were also identified in unaffected family members and, in some cases, they were not inherited by the affected children (reverse discordance), we hypothesised that these CNVs might contribute to the SLI susceptibility in a complex manner, acting as a risk factor with a reduced penetrance.

Lateralizations of brain structure and motor behavior have been observed in humans as early as the first trimester of gestation, and are likely to arise from asymmetrical genetic–developmental programs, as in other animals. Studies of gene expression levels in postmortem tissue samples, comparing the left and right sides of the human cerebral cortex, have generally not revealed striking transcriptional differences between the hemispheres. This is likely due to lateralization of gene expression being subtle and quantitative. However, a recent re-analysis and meta-analysis of gene expression data from the adult superior temporal and auditory cortex found lateralization of transcription of genes involved in synaptic transmission and neuronal electrophysiology. Meanwhile, human subcortical mid- and hindbrain structures have not been well studied in relation to lateralization of gene activity, despite being potentially important developmental origins of asymmetry. Genetic polymorphisms with small effects on adult brain and behavioral asymmetries are beginning to be identified through studies of large datasets, but the core genetic mechanisms of lateralized human brain development remain unknown. Identifying subtly lateralized genetic networks in the brain will lead to a new understanding of how neuronal circuits on the left and right are differently fine-tuned to preferentially support particular cognitive and behavioral functions.

Contains fulltext : 136035.pdf (Publisher’s version ) (Open Access) 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 (VBM) 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 10 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. 9 p.

Contains fulltext : 127593.pdf (Publisher’s version ) (Open Access) 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. 30 p.

Contains fulltext : 135963.pdf (Publisher’s version ) (Closed access) 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 x 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. Hum Brain Mapp 35:3277-3289, 2014. 13 p.

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia. ©2008 Macmillan Publishers Limited. All rights reserved., link_to_OA_fulltext