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Transl Psychiatry DOI:10.1038/tp.2015.99

Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia.

Publication TypeJournal Article
Year of Publication2015
AuthorsRees, E, Kirov, G, Walters, JT, Richards, AL, Howrigan, D, Kavanagh, DH, Pocklington, AJ, Fromer, M, Ruderfer, DM, Georgieva, L, Carrera, N, Gormley, P, Palta, P, Williams, H, Dwyer, S, Johnson, JS, Roussos, P, Barker, DD, Banks, E, Milanova, V, Rose, SA, Chambert, K, Mahajan, M, Scolnick, EM, Moran, JL, Tsuang, MT, Glatt, SJ, Chen, WJ, Hwu, H-G, Neale, BM, Palotie, A, Sklar, P, Purcell, SM, McCarroll, SA, Holmans, P, Owen, MJ, O'Donovan, MC
Corporate AuthorsTaiwanese Trios Exome Sequencing Consortium
JournalTransl Psychiatry
Volume5
Pagese607
Date Published2015 Jul 21
ISSN2158-3188
KeywordsCase-Control Studies, Exome, Family, Female, Gene Frequency, Genes, Recessive, Genetic Predisposition to Disease, Genotype, Heterozygote, Homozygote, Humans, Male, Schizophrenia, Voltage-Gated Sodium Channels
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.

URLhttp://dx.doi.org/10.1038/tp.2015.99
DOI10.1038/tp.2015.99
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26196440?dopt=Abstract

Alternate JournalTransl Psychiatry
PubMed ID26196440
PubMed Central IDPMC5068730
Grant ListU54 HG003067 / HG / NHGRI NIH HHS / United States
G0801418 / / Medical Research Council / United Kingdom
R01 MH071681 / MH / NIMH NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
WT098051 / / Wellcome Trust / United Kingdom
R01MH071681 / MH / NIMH NIH HHS / United States
WT089062 / / Wellcome Trust / United Kingdom
R01 MH099126 / MH / NIMH NIH HHS / United States
G0800509 / / Medical Research Council / United Kingdom
R01HG005827 / HG / NHGRI NIH HHS / United States
R01 HG005827 / HG / NHGRI NIH HHS / United States
MR/L010305/1 / / Medical Research Council / United Kingdom
R01 MH085521 / MH / NIMH NIH HHS / United States
R01MH085560 / MH / NIMH NIH HHS / United States
R01 MH085560 / MH / NIMH NIH HHS / United States
R01MH099126 / MH / NIMH NIH HHS / United States