Novel genetic loci underlying human intracranial volume identified through genome-wide association.
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LopezMichelle LucianoChristine MacareAndre MarquandMar MatarinKaren A MatherManuel MattheisenBernard MazoyerDavid R McKayRebekah McWhirterYuri MilaneschiNazanin Mirza-SchreiberRyan L MuetzelSusana Muñoz ManiegaKwangsik NhoAllison C NugentLoes M Olde LoohuisJaap OosterlaanMartina PapmeyerIrene PappaLukas PirpamerSara PudasBenno PützKumar B RajanAdaikalavan RamasamyJennifer S RichardsShannon L RisacherRoberto Roiz-SantiañezNanda RommelseEmma J RoseNatalie A RoyleTatjana RundekPhilipp G SämannClaudia L SatizabalLianne SchmaalAndrew J SchorkLi ShenJean ShinElena ShumskayaAlbert Vernon SmithEmma SprootenLachlan T StrikeAlexander TeumerRussell ThomsonDiana Tordesillas-GutierrezRoberto ToroDaniah TrabzuniDhananjay VaidyaJeroen Van der GrondDennis Van der MeerMarjolein M J Van DonkelaarKristel R Van EijkTheo G M van ErpDaan Van RooijEsther WaltonLars Tjelta WestlyeChristopher D WhelanBeverly G WindhamAnderson M WinklerGirma WoldehawariatChristiane WolfThomas WolfersBing XuLisa R YanekJingyun 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GrabeRobert C GreenOliver GruberVilmundur GudnasonSebastian GuelfiNarelle K HansellJohn HardyCatharina A HartmanRyota HashimotoKatrin HegenscheidAndreas HeinzStephanie Le HellardDena G HernandezDirk J HeslenfeldBeng-Choon HoPieter J HoekstraWolfgang HoffmannAlbert HofmanFlorian HolsboerGeorg HomuthNorbert HostenJouke-Jan HottengaHilleke E Hulshoff PolMasashi IkedaM Kamran IkramClifford R JackMark JenkinsonRobert JohnsonErik G JönssonJ Wouter JukemaRené S KahnRyota KanaiIwona KloszewskaDavid S KnopmanPeter KochunovJohn B KwokStephen M LawrieHervé LemaîtreXinmin LiuDan L LongoW T LongstrethOscar L LopezSimon LovestoneOliver MartinezJean-Luc MartinotVenkata S MattayColm McDonaldAndrew M McIntoshKatie L McmahonFrancis J McMahonPatrizia MecocciIngrid MelleAndreas Meyer-LindenbergSebastian MohnkeGrant W MontgomeryDerek W MorrisThomas H MosleyThomas W MühleisenBertram Müller-MyhsokMichael A NallsMatthias NauckThomas E NicholsWiro J NiessenMarkus M NöthenLars NybergKazutaka OhiRene L OlveraRoel A OphoffMassimo PandolfoTomas PausZdenka PausovaBrenda W J H PenninxGilbert Bruce PikeSteven G PotkinBruce M PsatySimone ReppermundMarcella RietschelJoshua L RoffmanNina Romanczuk-SeiferthJerome I RotterMina RytenRalph L SaccoPerminder Singh SachdevAndrew J SaykinReinhold SchmidtPeter R SchofieldSigurdur SigurdssonAndy SimmonsAndrew SingletonSanjay M SisodiyaColin SmithJordan W SmollerHilkka SoininenVelandai SrikanthVidar M SteenDavid J StottJessika E SussmannAnbupalam ThalamuthuHenning TiemeierArthur W TogaBryan J TraynorJuan TroncosoJessica A TurnerChristophe TzourioAndre G UitterlindenMaria C Valdés HernándezMarcel Van der BrugAad Van der LugtNic J A Van der WeeCornelia M Van DuijnNeeltje E M Van HarenDennis Van T EntMarie-Jose Van TolBadri N VardarajanDick J VeltmanMeike W VernooijHenry VölzkeHenrik WalterJoanna Marguerite WardlawThomas H WassinkMichael E WealeDaniel R WeinbergerMichael W WeinerWei WenEric WestmanTonya WhiteTien Y WongClinton B WrightH Ronald ZielkeAlan B ZondermanIan J DearyCharles DeCarliHelena SchmidtNicholas G MartinAnton J M De CraenMargaret J WrightLenore J LaunerGunter SchumannMyriam FornageBarbara FrankeStéphanie DebetteSarah E MedlandMohammad Arfan IkramPaul M ThompsonPublished in: Nature neuroscience (2016)
Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Keyphrases
- genome wide
- genome wide association study
- genome wide association
- optic nerve
- copy number
- dna methylation
- pi k akt
- systematic review
- endothelial cells
- body mass index
- signaling pathway
- cell proliferation
- gene expression
- randomized controlled trial
- young adults
- optical coherence tomography
- mental health
- multiple sclerosis
- cell cycle arrest
- early life