Emerging patterns of schizophrenia risk conferred by de novo mutation. D. Howrigan1,2, B. Neale1,2, K. Samocha1,2, J. Moran2, K. Chambert2, S. Rose2, M. Fromer2,3, S. Chandler4, N. Laird5, H. G. Hwu6, W. J. Chen6, S. Faraone7, S. Glatt7, M. Tsuang4, S. McCarroll8 1) Massachusetts General Hospital, Boston, MA; 2) Broad Institute, Cambridge, MA; 3) Mount Sinai School of Medicine, New York, NY; 4) University of California San Diego, La Jolla, CA; 5) Harvard School of Public Health, Boston, MA; 6) National Taiwan University, Taiwan; 7) SUNY Upstate Medical University, Syracuse, NY; 8) Harvard University, Cambridge, MA.

   Increased rates of deleterious de novo mutations have emerged as significant genetic risk factors among developmental disorders such as autism, intellectual disability, and epilepsy. In contrast, only modest effects of de novo mutation have been discovered so far among schizophrenia cohorts. In the current study, whole-exome sequencing has been performed on 1,110 complete trios from Taiwan with a sporadic schizophrenia diagnosis in the offspring. Exome sequencing data were generated using the Illumina HiSeq sequencing with the Agilent SureSelect exome capture platform, and validation of candidate de novo signals was analyzed using targeted high-throughput genotyping on Illumina HiSeq and Illumina MiSeq platforms. Confirmed de novo mutations were annotated using the NCBI RefSeq database. De novo mutation rates per trio and across the exome fall in line with the expected mutation rate. Using models that incorporate gene size and site-specific mutation rates into expectations of de novo mutation rates, we do not observe any single gene that surpasses exome-wide correction for multiple testing (set at p=1e-6). We do, however, see a significant enrichment of genes with multiple non-synonymous de novo mutations (empirical p=7e-4). When we combine our results with published de novo studies of schizophrenia, we observe nine genes with multiple loss-of-function events (empirical p<1e-4), and 87 genes with multiple missense events (empirical p=0.01). Gene set analyses also indicate that both loss-of-function and missense de novo mutations are enriched among targets of the Fragile X mental retardation protein (p=0.004 and p=6e-5, respectively) and among genes under evolutionary constraint (p=0.001 and p=2e-5, respectively). The current findings do not identify any single gene as an unequivocal risk factor for schizophrenia when disrupted by de novo mutation; however, aggregate analyses of genes hit with multiple damaging mutations and among well characterized gene sets in the literature indicate that significant patterns of de novo risk for schizophrenia are clearly emerging. We firmly believe larger cohorts and accumulation of de novo mutations in the literature will soon lead to specific genes being unequivocal risk factors, but remain aware that the increased liability due to de novo mutations comprises a modest fraction of the overall genetic liability in schizophrenia.

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