Exome arrays capture polygenic rare variant contributions to schizophrenia

Area of Science:

• Genetics
• Psychiatric Disorders

Background:

• Schizophrenia is a highly heritable psychiatric disorder.
• Genome-wide association studies (GWAS) have identified common risk loci, but rare alleles also contribute.
• Copy number variants (CNVs) and exome sequencing suggest involvement of rare genetic variants.

Purpose of the Study:

• To investigate the contribution of rare non-synonymous variants to schizophrenia risk using exome arrays.
• To analyze exome array data to identify associations between rare variants and schizophrenia susceptibility.
• To assess the enrichment of rare variant association signals in known schizophrenia risk genes and pathways.

Main Methods:

• Analysis of exome array data from 13,688 individuals (5,585 cases, 8,103 controls) from the UK.
• Examination of rare variants with minor allele frequency < 0.1%.
• Statistical analysis to identify enrichment of rare variant association signals in genome-wide significant loci and known rare variant gene sets.

Main Results:

• Rare variant association signals were enriched in genes mapping to autosomal loci significant in common variant GWAS for schizophrenia (PGWAS = 0.01).
• Enrichment was also observed in gene sets known to be enriched for rare variants in sequencing studies (PRARE = 0.026).
• The gene WDR88 (WD repeat-containing protein 88) showed gene-wise genome-wide significant support for association with schizophrenia (P = 6.5 × 10(-7)).

Conclusions:

• Rare alleles captured by exome chip arrays contribute to the genetic architecture of schizophrenia.
• While exome arrays offer a cost-effective way to sample rare variants, very large sample sizes are still required to fully elucidate their role.
• Further research with large cohorts is necessary to identify additional schizophrenia susceptibility alleles.