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 schizophrenia (SCZ) risk associated with DNMs has thus far has been modest. We analyzed DNMs from 1,695 SCZ affected trios and 1,077 published SCZ affected trios to better understand the 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 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.