@article {Fromer052209, author = {Menachem Fromer and Panos Roussos and Solveig K Sieberts and Jessica S Johnson and David H Kavanagh and Thanneer M Perumal and Douglas M Ruderfer and Edwin C Oh and Aaron Topol and Hardik R Shah and Lambertus L Klei and Robin Kramer and Dalila Pinto and Zeynep H G{\"u}m{\"u}{\c s} and A. Ercument Cicek and Kristen K Dang and Andrew Browne and Cong Lu and Li Xie and Ben Readhead and Eli A Stahl and Mahsa Parvisi and Tymor Hamamsy and John F Fullard and Ying-Chih Wang and Milind C Mahajan and Jonathan M.J. Derry and Joel Dudley and Scott E Hemby and Benjamin A Logsdon and Konrad Talbot and Towfique Raj and David A Bennett and Phil L De Jager and Jun Zhu and Bin Zhang and Patrick F Sullivan and Andrew Chess and Shaun M Purcell and Leslie A Shinobu and Lara M Mangravite and Hiroyoshi Toyoshiba and Raquel E Gur and Chang-Gyu Hahn and David A Lewis and Vahram Haroutonian and Mette A Peters and Barbara K Lipska and Joseph D Buxbaum and Eric E Schadt and Keisuke Hirai and Kathryn Roeder and Kristen J Brennand and Nicholas Katsanis and Enrico Dominici and Bernie Devlin and Pamela Sklar}, title = {Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia}, elocation-id = {052209}, year = {2016}, doi = {10.1101/052209}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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.}, URL = {https://www.biorxiv.org/content/early/2016/05/09/052209}, eprint = {https://www.biorxiv.org/content/early/2016/05/09/052209.full.pdf}, journal = {bioRxiv} }