Journal article
Genetic architecture of subcortical brain structures in 38,851 individuals
Nature genetics, Vol.51(11), pp.1624-1636
11/2019
DOI: 10.1038/s41588-019-0511-y
PMCID: PMC7055269
PMID: 31636452
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.
Details
- Title: Subtitle
- Genetic architecture of subcortical brain structures in 38,851 individuals
- Creators
- Claudia L Satizabal - Boston UniversityHieab H H Adams - Erasmus University RotterdamDerrek P Hibar - University of Southern CaliforniaCharles C White - Columbia UniversityMaria J Knol - Erasmus University RotterdamJason L Stein - University of Southern CaliforniaMarkus Scholz - Leipzig UniversityMuralidharan Sargurupremraj - Université de BordeauxNeda Jahanshad - University of Southern CaliforniaGennady V Roshchupkin - Erasmus University RotterdamAlbert V Smith - University of MichiganJoshua C Bis - University of WashingtonXueqiu Jian - The University of Texas Health Science Center at HoustonMichelle Luciano - University of EdinburghEdith Hofer - Medical University of GrazAlexander Teumer - Universitätsmedizin GreifswaldSven J van der Lee - Erasmus University RotterdamJingyun Yang - Rush University Medical CenterLisa R Yanek - Johns Hopkins MedicineTom V Lee - Baylor College of MedicineShuo Li - Boston UniversityYanhui Hu - Harvard UniversityJia Yu Koh - Singapore National Eye CenterJohn D Eicher - National Heart Lung and Blood InstituteSylvane Desrivières - King's College LondonAlejandro Arias-Vasquez - Radboud University NijmegenGanesh Chauhan - Université de BordeauxLavinia Athanasiu - University of OsloMiguel E Rentería - QIMR Berghofer Medical Research InstituteSungeun Kim - Indiana UniversityDavid Hoehn - Max Planck SocietyNicola J Armstrong - Murdoch UniversityQiang Chen - Lieber Institute for Brain DevelopmentAvram J Holmes - Yale UniversityAnouk den Braber - Vrije Universiteit AmsterdamIwona Kloszewska - Medical University of LodzMicael Andersson - Umeå UniversityThomas Espeseth - University of OsloOliver Grimm - Heidelberg UniversityLucija Abramovic - Utrecht UniversitySaud Alhusaini - Yale UniversityYuri Milaneschi - Vrije Universiteit AmsterdamMartina Papmeyer - University of EdinburghTomas Axelsson - Uppsala UniversityStefan Ehrlich - Technische Universität DresdenRoberto Roiz-Santiañez - Universidad de CantabriaBernd Kraemer - Heidelberg UniversityAsta K Håberg - Norwegian University of Science and TechnologyHannah J Jones - University of BristolG Bruce Pike - University of CalgaryDan J Stein - South African Medical Research CouncilAllison Stevens - Harvard UniversityJanita Bralten - Radboud University NijmegenMeike W Vernooij - Erasmus University RotterdamTamara B Harris - National Institutes of HealthIrina Filippi - Délégation Paris 5A Veronica Witte - Max Planck SocietyTulio Guadalupe - Max Planck SocietyKatharina Wittfeld - Universitätsmedizin GreifswaldThomas H Mosley - University of MississippiJames T Becker - University of PittsburghNhat Trung Doan - University of OsloSaskia P Hagenaars - University of EdinburghYasaman Saba - Medical University of GrazGabriel Cuellar-Partida - QIMR Berghofer Medical Research InstituteNajaf Amin - Erasmus University RotterdamSaima Hilal - National University of SingaporeKwangsik Nho - Indiana UniversityNazanin Mirza-Schreiber - Max Planck SocietyKonstantinos Arfanakis - Illinois Institute of TechnologyDiane M Becker - Johns Hopkins MedicineDavid Ames - The University of MelbourneAaron L Goldman - Lieber Institute for Brain DevelopmentPhil H Lee - Broad InstituteDorret I Boomsma - Vrije Universiteit AmsterdamSimon Lovestone - University of OxfordSudheer Giddaluru - University of BergenStephanie Le Hellard - University of BergenManuel Mattheisen - Stockholm Health Care ServicesMarc M Bohlken - Utrecht UniversityDalia Kasperaviciute - University College LondonLianne Schmaal - The University of MelbourneStephen M Lawrie - University of EdinburghIngrid Agartz - Karolinska InstitutetEsther Walton - University of BathDiana Tordesillas-Gutierrez - Marqués de Valdecilla University HospitalGareth E Davies - Avera HealthJean Shin - University of TorontoJonathan C Ipser - University of Cape TownLouis N Vinke - Boston UniversityMartine Hoogman - Radboud University NijmegenTianye Jia - King's College LondonRalph Burkhardt - Leipzig UniversityMarieke Klein - Radboud University NijmegenFabrice Crivello - Université de BordeauxDeborah Janowitz - Universitätsmedizin GreifswaldOwen Carmichael - Pennington Biomedical Research CenterUnn K Haukvik - University of OsloBenjamin S Aribisala - University of EdinburghHelena Schmidt - Medical University of GrazLachlan T Strike - The University of QueenslandChing-Yu Cheng - National University of SingaporeShannon L Risacher - Indiana UniversityBenno Pütz - Max Planck SocietyDebra A Fleischman - Rush University Medical CenterAmelia A Assareh - UNSW SydneyVenkata S Mattay - Johns Hopkins UniversityRandy L Buckner - Harvard UniversityPatrizia Mecocci - University of PerugiaAnders M Dale - University of California San DiegoSven Cichon - University of BaselMarco P Boks - Utrecht UniversityMar Matarin - University College LondonBrenda W J H Penninx - Vrije Universiteit AmsterdamVince D Calhoun - University of New MexicoM Mallar Chakravarty - McGill UniversityAndre F Marquand - Radboud University NijmegenChristine Macare - King's College LondonShahrzad Kharabian Masouleh - Institute for Neuroscience and Medicine: Brain and Behaviour (INM-7), Research Centre Jülich, Jülich, GermanyJaap Oosterlaan - Vrije Universiteit AmsterdamPhilippe Amouyel - Institut PasteurKatrin Hegenscheid - Universitätsmedizin GreifswaldJerome I Rotter - University of California, Los AngelesAndrew J Schork - Translational Genomics Research InstituteDavid C M Liewald - University of EdinburghGreig I de Zubicaray - Queensland University of TechnologyTien Yin Wong - National University of SingaporeLi Shen - University of PennsylvaniaPhilipp G Sämann - Max Planck SocietyHenry Brodaty - UNSW SydneyJoshua L Roffman - Harvard UniversityEco J C de Geus - Vrije Universiteit AmsterdamMagda Tsolaki - Aristotle University of ThessalonikiSusanne Erk - Humboldt-Universität zu BerlinKristel R van Eijk - University Medical Center UtrechtGianpiero L Cavalleri - Royal College of Surgeons in IrelandNic J A van der Wee - Leiden UniversityAndrew M McIntosh - University of EdinburghRandy L Gollub - Harvard UniversityKazima B Bulayeva - Dagestan State UniversityManon Bernard - University of TorontoJennifer S Richards - Radboud University NijmegenJayandra J Himali - Boston UniversityMarkus Loeffler - Leipzig UniversityNanda Rommelse - Radboud University NijmegenWolfgang Hoffmann - Universitätsmedizin GreifswaldLars T Westlye - University of OsloMaria C Valdés Hernández - University of EdinburghNarelle K Hansell - The University of QueenslandTheo G M van Erp - University of California, IrvineChristiane Wolf - University of WürzburgJohn B J Kwok - UNSW SydneyBruno Vellas - Université Fédérale de Toulouse Midi-PyrénéesAndreas Heinz - Charité - Universitätsmedizin BerlinLoes M Olde Loohuis - Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, USANorman Delanty - Royal College of Surgeons in IrelandBeng-Choon Ho - University of IowaChristopher R K Ching - University of Southern CaliforniaElena Shumskaya - Radboud University NijmegenBaljeet Singh - University of California, DavisAlbert Hofman - Harvard UniversityDennis van der Meer - Maastricht UniversityGeorg Homuth - Universitätsmedizin GreifswaldBruce M Psaty - University of WashingtonMark E Bastin - University of EdinburghGrant W Montgomery - The University of QueenslandTatiana M Foroud - Indiana UniversitySimone Reppermund - UNSW SydneyJouke-Jan Hottenga - Vrije Universiteit AmsterdamAndrew Simmons - Karolinska InstitutetAndreas Meyer-Lindenberg - Heidelberg UniversityWiepke Cahn - Utrecht UniversityChristopher D Whelan - University of Southern CaliforniaMarjolein M J van Donkelaar - Radboud University NijmegenQiong Yang - Boston UniversityNorbert Hosten - Universitätsmedizin GreifswaldRobert C Green - Harvard UniversityAnbupalam Thalamuthu - UNSW SydneySebastian Mohnke - Humboldt-Universität zu BerlinHilleke E Hulshoff Pol - University Medical Center UtrechtHonghuang Lin - Boston UniversityClifford R Jack Jr - Department of Radiology, Mayo Clinic, Rochester, MN, USAPeter R Schofield - UNSW SydneyThomas W Mühleisen - University of BaselPauline Maillard - University of California, DavisSteven G Potkin - University of California, IrvineWei Wen - UNSW SydneyEvan Fletcher - University of California, DavisArthur W Toga - University of Southern CaliforniaOliver Gruber - Heidelberg UniversityMatthew Huentelman - Translational Genomics Research InstituteGeorge Davey Smith - University of BristolLenore J Launer - National Institutes of HealthLars Nyberg - Umeå UniversityErik G Jönsson - Karolinska InstitutetBenedicto Crespo-Facorro - Universidad de CantabriaNastassja Koen - South African Medical Research CouncilDouglas N Greve - Harvard UniversityAndré G Uitterlinden - Erasmus University RotterdamDaniel R Weinberger - Johns Hopkins UniversityVidar M Steen - University of BergenIryna O Fedko - Vrije Universiteit AmsterdamNynke A Groenewold - University of Cape TownWiro J Niessen - Delft University of TechnologyRoberto Toro - Institut PasteurChristophe Tzourio - Centre Hospitalier Universitaire de BordeauxWilliam T Longstreth Jr - University of WashingtonM Kamran Ikram - Erasmus University RotterdamJordan W Smoller - Broad InstituteMarie-Jose van Tol - University Medical Center GroningenJessika E Sussmann - University of EdinburghTomas Paus - University of TorontoHervé Lemaître - Délégation Paris 5Matthias L Schroeter - Max Planck SocietyBernard Mazoyer - Université de BordeauxOle A Andreassen - University of OsloFlorian Holsboer - Max Planck SocietyChantal Depondt - Université Libre de BruxellesDick J Veltman - Vrije Universiteit AmsterdamJessica A Turner - Georgia State UniversityZdenka Pausova - University of TorontoGunter Schumann - King's College LondonDaan van Rooij - Radboud University NijmegenSrdjan Djurovic - University of BergenIan J Deary - University of EdinburghKatie L McMahon - Queensland University of TechnologyBertram Müller-Myhsok - University of LiverpoolRachel M Brouwer - Utrecht UniversityHilkka Soininen - University of Eastern FinlandMassimo Pandolfo - Université Libre de BruxellesThomas H Wassink - University of IowaJoshua W Cheung - University of Southern CaliforniaThomas Wolfers - Radboud University NijmegenJean-Luc Martinot - Délégation Paris 5Marcel P Zwiers - Radboud University NijmegenMatthias Nauck - Universitätsmedizin GreifswaldIngrid Melle - University of OsloNicholas G Martin - QIMR Berghofer Medical Research InstituteRyota Kanai - University College LondonEric Westman - Karolinska InstitutetRené S Kahn - Icahn School of Medicine at Mount SinaiSanjay M Sisodiya - University College LondonTonya White - Erasmus University RotterdamArvin Saremi - University of Southern CaliforniaHans van Bokhoven - Radboud University NijmegenHan G Brunner - Maastricht UniversityHenry Völzke - Universitätsmedizin GreifswaldMargaret J Wright - The University of QueenslandDennis van 't Ent - Vrije Universiteit AmsterdamMarkus M Nöthen - University of BonnRoel A Ophoff - University of California, Los AngelesJan K Buitelaar - Radboud University NijmegenGuillén Fernández - Radboud University NijmegenPerminder S Sachdev - UNSW SydneyMarcella Rietschel - Heidelberg UniversityNeeltje E M van Haren - Utrecht UniversitySimon E Fisher - Radboud University NijmegenAlexa S Beiser - Boston UniversityClyde Francks - Radboud University NijmegenAndrew J Saykin - Indiana UniversityKaren A Mather - UNSW SydneyNina Romanczuk-Seiferth - Charité - Universitätsmedizin BerlinCatharina A Hartman - University of GroningenAnita L DeStefano - Boston UniversityDirk J Heslenfeld - Vrije Universiteit AmsterdamMichael W Weiner - University of California, San FranciscoHenrik Walter - Humboldt-Universität zu BerlinPieter J Hoekstra - University of GroningenPaul A Nyquist - Johns Hopkins MedicineBarbara Franke - Radboud University NijmegenDavid A Bennett - Rush University Medical CenterHans J Grabe - Universitätsmedizin GreifswaldAndrew D Johnson - National Heart Lung and Blood InstituteChristopher Chen - National University of SingaporeCornelia M van Duijn - Leiden UniversityOscar L Lopez - University of PittsburghMyriam Fornage - The University of Texas Health Science Center at HoustonJoanna M Wardlaw - University of EdinburghReinhold Schmidt - Medical University of GrazCharles DeCarli - University of California, DavisPhilip L De Jager - Columbia UniversityArno Villringer - Max Planck SocietyStéphanie Debette - Université de BordeauxVilmundur Gudnason - University of IcelandSarah E Medland - QIMR Berghofer Medical Research InstituteJoshua M Shulman - Baylor College of MedicinePaul M Thompson - University of Southern CaliforniaSudha Seshadri - Boston UniversityM Arfan Ikram - Erasmus University Rotterdam
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.51(11), pp.1624-1636
- DOI
- 10.1038/s41588-019-0511-y
- PMID
- 31636452
- PMCID
- PMC7055269
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Grant note
- MR/S015132/1 / Medical Research Council MR/M013111/1 / Medical Research Council R01 HL120393 / NHLBI NIH HHS R01 AG015819 / NIA NIH HHS U01 AG049505 / NIA NIH HHS C06RR029965 / U.S. Department of Health & Human Services | NIH | National Center for Research Resources (NCRR) K99MH116115 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R03 AG054936 / NIA NIH HHS MC_QA137853 / Medical Research Council R01AG059874 / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R00 MH101367 / NIMH NIH HHS UL1 TR000153 / NCATS NIH HHS U01 AG052409 / NIA NIH HHS P30 AG010129 / NIA NIH HHS R01MH111671 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) U01 HL130114 / NHLBI NIH HHS U54 GM104940 / NIGMS NIH HHS R01 NS087541 / NINDS NIH HHS UH3 NS100605 / NINDS NIH HHS R01 AG017917 / NIA NIH HHS U01 HL120393 / NHLBI NIH HHS MC_UU_00011/1 / RCUK | MRC | Medical Research Foundation R01 MH119243 / NIMH NIH HHS R01 HL105756 / NHLBI NIH HHS G1001245 / Medical Research Council R01MH117601 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) MC_UU_00011/1 / Medical Research Council MC_PC_17228 / Medical Research Council BB/F019394/1 / Biotechnology and Biological Sciences Research Council K99MH102357 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) P30 AG010161 / NIA NIH HHS T32 AG058507 / NIA NIH HHS MR/N027558/1 / Medical Research Council R01 AG054076 / NIA NIH HHS
- Language
- English
- Date published
- 11/2019
- Academic Unit
- Psychiatry; Stead Family Department of Pediatrics
- Record Identifier
- 9984280875002771
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