Genetic architecture of subcortical brain structures in 38,851 individuals.

Claudia L Satizabal Hieab H H AdamsDerrek P HibarCharles C WhiteMaria J KnolJason L SteinMarkus ScholzMuralidharan SargurupremrajNeda JahanshadGennady V RoshchupkinAlbert V SmithJoshua C BisXueqiu JianMichelle LucianoEdith HoferAlexander Teumer Sven J Van der LeeJingyun YangLisa R YanekTom V LeeShuo LiYanhui HuJia Yu KohJohn D EicherSylvane DesrivieresAlejandro Arias-VasquezGanesh ChauhanLavinia AthanasiuMiguel E RenteriaSungeun KimDavid HoehnNicola J ArmstrongQiang ChenAvram J HolmesAnouk den BraberIwona KloszewskaMicael AnderssonThomas EspesethOliver GrimmLucija AbramovicSaud AlhusainiYuri MilaneschiMartina PapmeyerTomas AxelssonStefan EhrlichRoberto Roiz-SantiañezBernd KraemerAsta K HåbergHannah J Jones Gilbert Bruce Pike Dan J SteinAllison StevensJanita BraltenMeike W VernooijTamara B HarrisIrina FilippiA Veronica WitteTulio GuadalupeKatharina WittfeldThomas H MosleyJames T BeckerNhat Trung DoanSaskia P HagenaarsYasaman SabaGabriel Cuellar-PartidaNajaf AminSaima HilalKwangsik NhoNazanin Mirza-SchreiberKonstantinos ArfanakisDiane M BeckerDavid AmesAaron L GoldmanPhil H LeeDorret I BoomsmaSimon LovestoneSudheer GiddaluruStephanie Le HellardManuel MattheisenMarc M BohlkenDalia KasperaviciuteLianne SchmaalStephen M LawrieIngrid AgartzEsther WaltonDiana Tordesillas-GutierrezGareth E DaviesJean ShinJonathan C IpserLouis N VinkeMartine HoogmanTianye Jia Ralph Burkhardt Marieke Klein Stephanie Debette Deborah JanowitzOwen CarmichaelUnn K HaukvikBenjamin S AribisalaHelena SchmidtLachlan T StrikeChing-Yu ChengShannon L RisacherBenno PützDebra A FleischmanAmelia A AssarehVenkata S MattayRandy L BucknerPatrizia MecocciAnders M DaleSven CichonMarco P M BoksMar MatarinBrenda W J H PenninxVince D CalhounM Mallar ChakravartyAndre F MarquandChristine MacareShahrzad Kharabian MasoulehJaap OosterlaanPhillippe AmouyelKatrin HegenscheidJerome I RotterAndrew J SchorkDavid C M Liewald Greig I de ZubicarayTien Yin WongLi ShenPhilipp G SämannHenry BrodatyJoshua L RoffmanEco J C de GeusMagda TsolakiSusanne ErkKristel R van EijkGianpiero L CavalleriNic J A van der WeeAndrew M McIntoshRandy L GollubKazima B BulayevaManon BernardJennifer S RichardsJayanadra J HimaliMarkus LoefflerNanda RommelseWolfgang HoffmannLars Tjelta WestlyeMaria C Valdés HernándezNarelle K Hansell Theo G M van ErpChristiane WolfJohn B J KwokBruno VellasAndreas HeinzLoes M Olde LoohuisNorman DelantyBeng-Choon HoChristopher R K ChingElena ShumskayaBaljeet SinghAlbert HofmanDennis van der MeerGeorg HomuthBruce M PsatyMark E BastinGrant W MontgomeryTatiana M ForoudSimone ReppermundJouke-Jan HottengaAndrew SimmonsAndreas Meyer-Lindenberg Wiepke CahnChristopher D WhelanMarjolein M J Van Donkelaar Qiong YangNorbert HostenRobert C GreenAnbupalam ThalamuthuSebastian MohnkeHilleke E Hulshoff PolHonghuang LinClifford R JackPeter R Schofield Thomas W MühleisenPauline MaillardSteven G PotkinWei WenEvan FletcherArthur W TogaOliver GruberMatthew HuentelmanGeorge Davey SmithLenore J LaunerLars NybergErik G JönssonBenedicto Crespo-FacorroNastassja KoenDouglas N GreveAndre G Uitterlinden Daniel R WeinbergerVidar M SteenIryna O FedkoNynke A GroenewoldWiro J NiessenRoberto ToroChristophe TzourioWilliam T LongstrethM Kamran IkramJordan W SmollerMarie-Jose van TolJessika E SussmannTomas PausHervé LemaîtreMatthias L SchroeterBernard Mazoyer Ole Andreas AndreassenFlorian HolsboerChantal DepondtDick J VeltmanJessica A TurnerZdenka PausovaGunter SchumannDaan van RooijSrdjan DjurovicIan J DearyKatie L McmahonBertram Müller-MyhsokRachel M BrouwerHilkka SoininenMassimo PandolfoThomas H WassinkJoshua W CheungThomas WolfersJean-Luc MartinotMarcel P ZwiersMatthias NauckIngrid MelleNicholas G MartinRyota KanaiErik WestmanRené S KahnSanjay M SisodiyaTonya WhiteArvin SaremiHans van BokhovenHan G BrunnerHenry VölzkeMargaret J WrightDennis van 't EntMarkus M NöthenRoel A OphoffJan K BuitelaarGuillén FernándezPerminder Singh Sachdev Marcella D C RietschelNeeltje E M van HarenSimon E FisherAlexa S BeiserClyde FrancksAndrew J SaykinKaren A MatherNina Romanczuk-SeiferthCatharina A HartmanAnita L DeStefanoDirk J HeslenfeldMichael W WeinerHenrik WalterPieter J HoekstraPaul A NyquistBarbara FrankeDavid A BennettHans Jörgen GrabeAndrew D JohnsonChristopher ChenCornelia M van DuijnOscar L LopezMyriam FornageJoanna Marguerite WardlawReinhold SchmidtCharles DeCarliPhilip Lawrence De JagerArno VillringerStéphanie DebetteVilmundur G Gudnason Sarah E MedlandJoshua M ShulmanPaul M ThompsonSudha SeshadriMohammad Arfan Ikram

Published in: Nature genetics (2019)

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.