PT - JOURNAL ARTICLE AU - Menachem Fromer AU - Panos Roussos AU - Solveig K Sieberts AU - Jessica S Johnson AU - David H Kavanagh AU - Thanneer M Perumal AU - Douglas M Ruderfer AU - Edwin C Oh AU - Aaron Topol AU - Hardik R Shah AU - Lambertus L Klei AU - Robin Kramer AU - Dalila Pinto AU - Zeynep H Gümüş AU - A. Ercument Cicek AU - Kristen K Dang AU - Andrew Browne AU - Cong Lu AU - Li Xie AU - Ben Readhead AU - Eli A Stahl AU - Mahsa Parvisi AU - Tymor Hamamsy AU - John F Fullard AU - Ying-Chih Wang AU - Milind C Mahajan AU - Jonathan M.J. Derry AU - Joel Dudley AU - Scott E Hemby AU - Benjamin A Logsdon AU - Konrad Talbot AU - Towfique Raj AU - David A Bennett AU - Phil L De Jager AU - Jun Zhu AU - Bin Zhang AU - Patrick F Sullivan AU - Andrew Chess AU - Shaun M Purcell AU - Leslie A Shinobu AU - Lara M Mangravite AU - Hiroyoshi Toyoshiba AU - Raquel E Gur AU - Chang-Gyu Hahn AU - David A Lewis AU - Vahram Haroutonian AU - Mette A Peters AU - Barbara K Lipska AU - Joseph D Buxbaum AU - Eric E Schadt AU - Keisuke Hirai AU - Kathryn Roeder AU - Kristen J Brennand AU - Nicholas Katsanis AU - Enrico Dominici AU - Bernie Devlin AU - Pamela Sklar TI - Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia AID - 10.1101/052209 DP - 2016 Jan 01 TA - bioRxiv PG - 052209 4099 - http://biorxiv.org/content/early/2016/05/09/052209.short 4100 - http://biorxiv.org/content/early/2016/05/09/052209.full AB - Over 100 genetic loci harbor schizophrenia associated variants, yet how these common variants confer risk is uncertain. The CommonMind Consortium has sequenced dorsolateral prefrontal cortex RNA from schizophrenia cases (n=258) and control subjects (n=279), creating the largest publicly available resource to date of gene expression and its genetic regulation; ∼5 times larger than the latest release of GTEx. Using this resource, we find that ∼20% of the schizophrenia risk loci have common variants that could explain regulation of brain gene expression. In five loci, these variants modulate expression of a single gene: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Experimentally altered expression of three of them, FURIN, TSNARE1, and CNTN4, perturbs the proliferation and apoptotic index of neural progenitors and leads to neuroanatomical deficits in zebrafish. Furthermore, shRNA mediated knock-down of FURIN1 in neural progenitor cells derived from human induced pluripotent stem cells produces abnormal neural migration. Although 4.2% of genes (N = 693) display significant differential expression between cases and controls, 44% show some evidence for differential expression. All fold changes are ≤ 1.33, and an independent cohort yields similar differential expression for these 693 genes (r = 0.58). These findings are consistent with schizophrenia being highly polygenic, as has been reported in investigations of common and rare genetic variation. Co-expression analyses identify a gene module that shows enrichment for genetic associations and is thus relevant for schizophrenia. Taken together, these results pave the way for mechanistic interpretations of genetic liability for schizophrenia and other brain diseases.