Genome-wide burden of deleterious coding variants increased in schizophrenia

Abstract

Schizophrenia is a common complex disorder with polygenic inheritance. Here we show that by using an approach that compares the individual loads of rare variants in 1,042 schizophrenia cases and 961 controls, schizophrenia cases carry an increased burden of deleterious mutations. At a genome-wide level, our results implicate non-synonymous, splice site as well as stop-altering single-nucleotide variations occurring at minor allele frequency of ≥ 0.01% in the population. In an independent replication sample of 5,585 schizophrenia cases and 8,103 controls of European ancestry we confirm an enrichment in cases of the alleles identified in our study. In addition, the genes implicated by the increased burden of rare coding variants highlight the involvement of neurodevelopment in the aetiology of schizophrenia.

Figure 1. Set-unique SNVs.

Diagram depicting the set-unique variants (not to scale, cases n=1,002, controls n=931). The set NS represents all variants that are scored by ISUB, and the set DEL includes only those variants that are predicted to be deleterious. In particular, the set DEL includes stop-altering and splice site variants.