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Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia
- Source :
- Translational Psychiatry, Translational psychiatry, vol 5, iss 7
- Publication Year :
- 2015
-
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.
- Subjects :
- Nonsynonymous substitution
Male
INTELLECTUAL DISABILITY
LOCI
Genome-wide association study
Voltage-Gated Sodium Channels
VARIANTS
Compound heterozygosity
3124 Neurology and psychiatry
0302 clinical medicine
Gene Frequency
2.1 Biological and endogenous factors
Medicine
Psychology
Exome
HOMOZYGOSITY
Aetiology
Exome sequencing
Genetics
Psychiatry
RISK
0303 health sciences
Homozygote
Serious Mental Illness
Psychiatry and Mental health
Mental Health
Public Health and Health Services
Female
Original Article
Taiwanese Trios Exome Sequencing Consortium
Life Sciences & Biomedicine
Heterozygote
Genotype
Intellectual and Developmental Disabilities (IDD)
Clinical Sciences
Genes, Recessive
03 medical and health sciences
Cellular and Molecular Neuroscience
Clinical Research
Recessive
Humans
Family
Genetic Predisposition to Disease
Allele
GENOME-WIDE ASSOCIATION
AUTISM
Allele frequency
Biological Psychiatry
030304 developmental biology
SPECTRUM
Science & Technology
business.industry
Human Genome
Brain Disorders
Minor allele frequency
CONSANGUINITY
Genes
DE-NOVO MUTATIONS
Case-Control Studies
RC0321
Schizophrenia
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 21583188
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Translational psychiatry
- Accession number :
- edsair.doi.dedup.....5b192092c4e6fde38c1b01cefd08b6b6