The genetic architecture of the human cerebral cortex

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0,361

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Résumé

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P < 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P < 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS

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La notice

Revue

Science

Thématique

Genetic Associations and Epidemiology

Domaine

Biochemistry, Genetics and Molecular Biology

Établissements canadiens

Holland Bloorview Kids Rehabilitation HospitalUniversity of CalgaryMcGill UniversityDouglas Mental Health University InstituteMontreal Neurological Institute and HospitalUniversity of TorontoSickKids FoundationHospital for Sick Children

Organismes subventionnaires

CilagFP7 Ideas: European Research CouncilNIH Clinical CenterU.S. National Library of MedicineNational Institute of Biomedical Imaging and BioengineeringNational Institute of Neurological Disorders and StrokeNational Institute of General Medical SciencesNational Institute of Mental HealthNational Institute on AgingNational Human Genome Research InstituteHelmholtz Zentrum MünchenEuropean Regional Development FundNational Health and Medical Research CouncilBiotechnology and Biological Sciences Research CouncilEuropean Social FundMedical Research CouncilMaryland Population Research Center, University of MarylandHorizon 2020 Framework ProgrammeUniversity of California, IrvineUniversity of California, San DiegoGillings School of Public HealthDirectorate-General for Research and InnovationGenentechDirectorate for Biological SciencesNational Institutes of HealthMax Planck Instituut voor PsycholinguïstiekMacquarie Group FoundationHeinz Nixdorf StiftungEpilepsy SocietyIXICOFreistaat SachsenDamp StiftungServierNational Healthcare GroupInstituto de Investigación Marqués de ValdecillaMedizinische Universität GrazNational Center for Research ResourcesFederalno Ministarstvo Obrazovanja i NaukeMutuelle Générale de l'Education NationaleUniversidade Estadual de CampinasUniversité de BordeauxUniversity of New South WalesRadboud Universitair Medisch CentrumUniversitair Medisch Centrum GroningenUniversitetet i BergenHelse Midt-NorgeOesterreichische NationalbankF. Hoffmann-La RocheUniversity of TorontoStanley Medical Research InstituteScience and Technology Commission of Shanghai MunicipalityUniversity College London Hospitals NHS Foundation TrustErasmus Medisch CentrumRadboud UniversiteitRussian Foundation for Basic ResearchVrije Universiteit AmsterdamNeuraxpharmVetenskapsrådetNorges Teknisk-Naturvitenskapelige UniversitetUniversiteit UtrechtMinistry of Education of the People's Republic of ChinaZonMwNSW HealthNational Natural Science Foundation of ChinaNational Medical Research CouncilNorges ForskningsrådSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungStockholms Läns LandstingNational Heart, Lung, and Blood InstituteUniversiteit LeidenH. Lundbeck A/SEuropean Federation of Pharmaceutical Industries and AssociationsInstitut National de la Santé et de la Recherche MédicaleAustralian Schizophrenia Research BankNederlandse Organisatie voor Wetenschappelijk OnderzoekDeutsche ForschungsgemeinschaftUniversity of GalwayScience Foundation IrelandFundação de Amparo à Pesquisa do Estado de São PauloCanadian Institutes of Health ResearchKnut och Alice Wallenbergs StiftelseEuropean CommissionScottish Funding CouncilMassachusetts General HospitalUniversity College LondonHelse Sør-Øst RHFMax-Planck-GesellschaftKing's College LondonNational Institute of Diabetes and Digestive and Kidney DiseasesLieber Institute for Brain DevelopmentAlzheimer's AssociationPfizerEU Joint Programme – Neurodegenerative Disease ResearchFresenius Medical Care North AmericaQIMR Berghofer Medical Research InstituteAustrian Science FundNational Institute for Health and Care ResearchPratt FoundationTrinity College DublinUniversity of BristolFoundation for the National Institutes of HealthNational Alliance for Research on Schizophrenia and DepressionHealth Research BoardNorthern California Institute for Research and EducationMichael J. Fox Foundation for Parkinson's ResearchSanofiEisaiLeids Universitair Medisch CentrumDevelopment of Innovative Strategies for a Transdisciplinary approach to ALZheimer's diseaseSunovionSylvia and Charles Viertel Charitable FoundationNovartis Pharmaceuticals CorporationAlzheimer's Disease Neuroimaging InitiativeCentre for Cognitive Ageing and Cognitive EpidemiologySimons FoundationSchool of Medicine, Boston UniversityAgence Nationale de la RechercheWellcome TrustFondation de l'Avenir pour la Recherche Médicale AppliquéeNational Institute on Drug AbuseAge UKEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentUniversity of Southern CaliforniaMission Interministérielle de Lutte Contre les Drogues et les Conduites AddictivesFondation LeducqNational Science FoundationBioClinicaKavli FoundationRamsay Health CareBiogenHersenstichtingU.S. Department of DefenseEli Lilly and CompanyBristol-Myers SquibbU.S. Department of Health and Human ServicesMayo ClinicGlaxoSmithKlineKarolinska InstitutetU.S. Department of Veterans AffairsU.S. Department of EnergyCardiff UniversityHoward Hughes Medical InstituteMeso Scale DiagnosticsFondation pour la Recherche MédicaleSouth London and Maudsley NHS Foundation TrustFondation de FranceBrain and Behavior Research FoundationNational Center for Advancing Translational SciencesBundesministerium für Bildung und ForschungBergens ForskningsstiftelseKarl-Franzens-Universität GrazSvenska Forskningsrådet FormasCenter of Excellence for Stress and Mental Health

Mots-clés

NeuroscienceCerebral cortexBiologyCortex (anatomy)Functional magnetic resonance imagingHuman brainGenetic architectureGeneGeneticsQuantitative trait locus

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