Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia
Journal
Translational psychiatry
Journal Volume
5
Pages
e607
Date Issued
2015
Author(s)
Kirov G.
Walters J.T.
Richards A.L.
Howrigan D.
Kavanagh D.H.
Pocklington A.J.
Fromer M.
Ruderfer D.M.
Georgieva L.
Carrera N.
Gormley P.
Palta P.
Williams H.
Dwyer S.
Johnson J.S.
Roussos P.
Barker D.D.
Banks E.
Milanova V.
Rose S.A.
Chambert K.
Mahajan M.
Scolnick E.M.
Moran J.L.
Tsuang M.T.
Glatt S.J.
Chen W.J.
Taiwanese Trios Exome Sequencing Consortium, Neale B.M.
Palotie A.
Sklar P.
Purcell S.M.
McCarroll S.A.
Holmans P.
Owen M.J.
O'Donovan M.C.
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.
SDGs
Type
journal article