RT Journal Article
SR Electronic
T1 Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 052209
DO 10.1101/052209
A1 Menachem Fromer
A1 Panos Roussos
A1 Solveig K Sieberts
A1 Jessica S Johnson
A1 David H Kavanagh
A1 Thanneer M Perumal
A1 Douglas M Ruderfer
A1 Edwin C Oh
A1 Aaron Topol
A1 Hardik R Shah
A1 Lambertus L Klei
A1 Robin Kramer
A1 Dalila Pinto
A1 Zeynep H Gümüş
A1 A. Ercument Cicek
A1 Kristen K Dang
A1 Andrew Browne
A1 Cong Lu
A1 Li Xie
A1 Ben Readhead
A1 Eli A Stahl
A1 Mahsa Parvisi
A1 Tymor Hamamsy
A1 John F Fullard
A1 Ying-Chih Wang
A1 Milind C Mahajan
A1 Jonathan M.J. Derry
A1 Joel Dudley
A1 Scott E Hemby
A1 Benjamin A Logsdon
A1 Konrad Talbot
A1 Towfique Raj
A1 David A Bennett
A1 Phil L De Jager
A1 Jun Zhu
A1 Bin Zhang
A1 Patrick F Sullivan
A1 Andrew Chess
A1 Shaun M Purcell
A1 Leslie A Shinobu
A1 Lara M Mangravite
A1 Hiroyoshi Toyoshiba
A1 Raquel E Gur
A1 Chang-Gyu Hahn
A1 David A Lewis
A1 Vahram Haroutonian
A1 Mette A Peters
A1 Barbara K Lipska
A1 Joseph D Buxbaum
A1 Eric E Schadt
A1 Keisuke Hirai
A1 Kathryn Roeder
A1 Kristen J Brennand
A1 Nicholas Katsanis
A1 Enrico Dominici
A1 Bernie Devlin
A1 Pamela Sklar
YR 2016
UL http://biorxiv.org/content/early/2016/05/09/052209.abstract
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.