Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia

Abstract

Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome‐wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF] < 0.001) in genes intolerant of loss‐of‐function (LoF) variation and in genes whose messenger RNAs bind to fragile X mental retardation protein (FMRP). We further delineate the genetic architecture of schizophrenia by excluding a role for uncommon exomic variants (0.01 ≤ MAF ≥ 0.001) that confer a relatively large effect (odds ratio [OR] > 4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studies.

Genetic association of FMRP targets with psychiatric disorders

“…This same relationship was reflected in analyses of bipolar disorder and major depressive disorder risk alleles. Our observations are consistent with previous gene set analyses of FMRP targets in the context of schizophrenia (11)(12)(13)(14)(15) and major depressive disorder (21), but whilst FMRP targets have been previously linked to bipolar disorder through rare coding variants (35), our findings provide novel evidence linking FMRP targets to bipolar disorder through common variation.…”

“…FMRP targets have likewise been associated with schizophrenia through rare genetic variants (12)(13)(14)(15). We used exome sequencing data to determine which bins of genes were associated with schizophrenia through rare and de novo coding variants.…”

“…The mRNA targets of FMRP have received additional attention from psychiatric research due to their enrichment for genes harbouring risk to psychiatric disorders. A set of 842 highconfidence FMRP targets, originating from a study by Darnell et al in 2011 (1), have been reported to be enriched for genetic association with schizophrenia (10)(11)(12)(13)(14)(15)(16), autism (17)(18)(19)(20) and major depressive disorder (21). In the case of schizophrenia, not only is this association robust across genome-wide association studies, but it is also mirrored across studies of multiple types of genetic mutation (common and rare) conferring risk to the disorder (10)(11)(12)(13)(14)(15)(16).…”

Psychiatric Genomics: An Update and an Agenda

“…SETD1A is the only gene implicated to date by whole exome sequencing studies (35), but other such studies have only found hints of biological pathways by focusing on extremely rare variation (36, 37). It was widely anticipated that exon variation in the 0.005 to 0.01 allele frequency range would be readily found but this has not been observed (38), and a recent study of height required over 700,000 subjects to identify loci in this range (39). In a direct comparison, common variation had 14–28 times more impact on risk for schizophrenia than rare CNVs or rare exonic variation (40).…”

Recent Advances in the Genetics of Schizophrenia

“…The corresponding RNAs included many known to interact with synaptic proteins, so they concluded that these rare genetic variants disrupt synaptic function. Most recently, Leonenko et al [85] reported on 10,011 schizophrenia cases and 13,791 controls. They found that in schizophrenia, genes intolerant of loss-of-function variation and genes whose RNAs bind FMRP, similar to CNV results, carried an excess of rare alleles with minor allele frequency less than 0.1%.…”