Exome Sequencing in Schizophrenia-Affected Parent–offspring Trios Reveals Risk Conferred by Protein-Coding De Novo Mutations

Abstract

Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas association with schizophrenia (SCZ) risk thus far has been modest. We analyze whole-exome sequence from 1,695 SCZ affected trios along with DNMs from 1,077 published SCZ trios to better understand their contribution to SCZ risk. Among 2,772 SCZ probands, exome-wide DNM burden remains modest. Gene set analyses reveal that SCZ DNMs are significantly concentrated in genes either highly brain expressed, under strong evolutionary constraint, and/or overlap with genes identified in other neurodevelopmental disorders. No single gene surpasses exome-wide significance, however sixteen genes are recurrently hit by protein-truncating DNMs, a 3.15-fold higher rate than the mutation model expectation (permuted 95% CI=1-10 genes, permuted p=3e-5). Overall, DNMs explain only a small fraction of SCZ risk, and larger samples are needed to identify individual risk genes, as coding variation across many genes confer risk for SCZ in the population.