Schizophrenia risk conferred by protein-coding de novo mutations

Abstract

Protein-coding de novo mutations (DNMs) in the form of single nucleotide changes and short insertions/deletions are significant genetic risk factors for autism, intellectual disability, developmental delay, and epileptic encephalopathy. In contrast, the burden of DNMs has thus far only had a modest documented impact on schizophrenia (SCZ) risk. Here, we analyze whole-exome sequence from 1,695 SCZ affected parent-offspring trios from Taiwan along with DNMs from 1,077 published SCZ trios to better understand the contribution of coding DNMs to SCZ risk. Among 2,772 SCZ affected probands, the increased burden of DNMs is modest. Gene set analyses show that the modest increase in risk from DNMs in SCZ probands is concentrated in genes that are either highly brain expressed, under strong evolutionary constraint, and/or overlap with genes identified as DNM risk factors in other neurodevelopmental disorders. No single gene meets the criteria for genome-wide significance, but we identify 16 genes that are recurrently hit by a protein-truncating DNM, which is a 3.15-fold higher rate than mutation model expectation of 5.1 genes (permuted 95% CI=1-10 genes, permuted p=3e-5). Overall, DNMs explain only a small fraction of SCZ risk, and this risk is polygenic in nature suggesting that coding variation across many different genes will be a risk factor for SCZ in the population.

Extreme Polygenicity of Complex Traits Is Explained by Negative Selection

“…Other traits may have completely different de novo effect size distributions; for example, schizophrenia has much weaker total de novo enrichment, and de novo point mutations have unclear penetrance and polygenicity. 56,57 This question could be addressed by estimating polygenicity for increasingly rare variants. We only analyzed SNPs at allele frequencies greater than 0.005, due to poor imputation accuracy at lower frequencies.…”

Analyses of rare and common alleles in parent-proband trios implicate rare missense variants in SLC6A1 in schizophrenia and confirm the involvement of loss of function intolerant and neurodevelopmental disorder genes

“…Missense-damaging mutation rates for individual genes were calculated by summing tri-nucleotide mutation probabilities for all sites with an MPC score ≥ 2. Following previous work by us and others 14,15 , if an individual carried multiple de novo variants in the same gene, we conservatively considered these to be the result of a single mutation event, and retained for analysis only the variant predicted to be most deleterious.…”

“…This is partly because of lower statistical power, as the number of trios that have been exome-sequenced in studies of schizophrenia (n=2,834) is smaller than equivalent studies of DD (n=7,580) 10 and ASD (n = 6,430) 8 , but it also reflects the weaker enrichment in schizophrenia for this type of variant. As a set, genes disrupted by DNVs in NDDs are also enriched for DNVs in schizophrenia 14,15 , and therefore it follows that some of the genes implicated in ASD and DD by RCVs are also involved in the aetiology of schizophrenia. Aiming to contribute to the schizophrenia rare variant discovery effort, we have undertaken exome-sequencing in a new sample of 613 schizophrenia trios, and combined our data with published data from 2,834 trios, which includes 617 trios previously sequenced by our group 14 , to provide the largest analysis of coding DNVs in schizophrenia to date.…”

De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia

“…When combined with our new trios, this resulted in a sample size of 3,444 schizophrenia trios. No statistical methods were used to pre-determine sample sizes but our trio sample is the largest reported to date and consists of all publicly available data from exome-sequencing studies of de novo variants in schizophrenia 15,16 . We note that no DNV from our new trios was also observed among the previously published schizophrenia de novo data, thus confirming the independence of our new trio dataset.…”