Gene expression elucidates functional impact of polygenic risk for schizophrenia.
Menachem FromerPanos RoussosSolveig K SiebertsJessica S JohnsonDavid H KavanaghThanneer M PerumalDouglas M RuderferEdwin C OhAaron TopolHardik R ShahLambertus L KleiRobin KramerDalila PintoZeynep H GümüşA Ercument CicekKristen K DangAndrew BrowneCong LuLu XieBen ReadheadEli A StahlJianqiu XiaoMahsa ParviziTymor HamamsyJohn F FullardYing-Chih WangMilind C MahajanJonathan M J DerryJoel T DudleyScott E HembyBenjamin A LogsdonKonrad TalbotTowfique RajDavid A BennettPhilip L De JagerJun ZhuBin ZhangPatrick F SullivanAndrew ChessShaun M PurcellLeslie A ShinobuLara M MangraviteHiroyoshi ToyoshibaRaquel E GurChang-Gyu HahnDavid A LewisVahram HaroutunianMette A PetersBarbara K LipskaJoseph D BuxbaumEric E SchadtKeisuke HiraiKathryn RoederKristen J BrennandNicholas KatsanisEnrico DomeniciBernie DevlinPamela SklarPublished in: Nature neuroscience (2016)
Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ≤ 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.