@article{58a45a8242d24b08980f03dd8fd292b4,
title = "Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia",
abstract = "Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband–parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽ 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 × 10−4). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽ 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.",
author = "E. Rees and G. Kirov and Walters, {J. T.} and Richards, {A. L.} and D. Howrigan and Kavanagh, {D. H.} and Pocklington, {A. J.} and M. Fromer and Ruderfer, {D. M.} and L. Georgieva and N. Carrera and P. Gormley and P. Palta and H. Williams and S. Dwyer and Johnson, {J. S.} and P. Roussos and Barker, {D. D.} and E. Banks and V. Milanova and Rose, {S. A.} and K. Chambert and M. Mahajan and Scolnick, {E. M.} and Moran, {J. L.} and Tsuang, {M. T.} and Glatt, {S. J.} and Chen, {W. J.} and Hwu, {H. G.} and Neale, {B. M.} and A. Palotie and P. Sklar and Purcell, {S. M.} and McCarroll, {S. A.} and P. Holmans and Owen, {M. J.} and O{\textquoteright}donovan, {M. C.}",
note = "Funding Information: Work in Cardiff was supported by Medical Research Council Centre (G0800509) and Program Grants (G0801418) and the European Community{\textquoteright}s Seventh Framework Programme (HEALTH-F2-2010-241909 (Project EU-GEI)). Work at the Icahn School of Medicine at Mount Sinai was supported by the Friedman Brain Institute, the Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department of Scientific Computing) and National Institutes of Health grants R01HG005827 (SMP), R01MH099126 (SMP) and R01MH071681 (PS). Work at the Broad Institute was funded by Fidelity Foundations, the Sylvan Herman Foundation, philanthropic gifts from Kent and Liz Dauten, Ted and Vada Stanley and an anonymous donor to the Stanley Center for Psychiatric Research. Work at the Wellcome Trust Sanger Institute was supported by The Wellcome Trust (grant numbers WT089062 and WT098051) and also by the European Commission FP7 project gEUVADIS no. 261123 (PP). Work on the Taiwanese trios was supported by NIH/NHGRI grant U54HG003067 (Eric S Lander, Principal Investigator (PI)), NIMH grants R01 MH085521 (SJG, PI) and R01 MH085560 (MTT, PI), a grant from the Gerber Foundation (SJG, PI), a grant from the Sidney R. Baer, Jr. Foundation (SJG, PI) grants from NARSAD: The Brain and Behavior Research Foundation (SJG and MTT, PIs) and the Stanley Center for Psychiatric Research. Publisher Copyright: {\textcopyright} 2015, Springer Nature. All rights reserved.",
year = "2015",
month = jul,
doi = "10.1038/TP.2015.99",
language = "English",
volume = "5",
journal = "Translational Psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",
number = "7",
}