Abstract

Background Schizophrenia is a debilitating psychiatric disorder that affects nearly 1% of the population. Schizophrenia has been demonstrated to have a substantial genetic component, with common and rare variants contributing to individual risk. While Genome-Wide Association Studies have implicated over a 140 common risk loci for schizophrenia, rare variant analyses from sequencing studies have had limited success in implicating individual genes, presumably owing to power limitations. Methods Here, we present the Schizophrenia Exome Meta-Analysis (SCHEMA) Consortium, a large multi-site collaboration to aggregate, generate, and analyze high-throughput sequencing data of schizophrenia to advance gene discovery. To date, we have sequenced and processed the whole exomes of over 20,000 schizophrenia cases and 45,000 matched controls using a standardized variant calling and QC pipeline based on GATK and Hail, yielding one of the largest sequencing data sets of a complex trait to date. Our study actively recruited from diverse global populations, and includes individuals of European, Latin American, East Asian, Ashkenazi Jewish, and African American ancestry. Because our exomes were sequenced with various capture technologies over seven years, we developed a novel pipeline to estimate exon-by-exon coverage of all sequencing batches in our data set, and incorporated this information in quality control and analysis. After adjusting for local differences in coverage, we observed comparable quality metrics between different cohorts and sequencing waves. Results We first replicated findings from earlier sequencing studies of schizophrenia, including a substantial enrichment of ultra-rare damaging variants in genes with a near-completion depletion of protein-truncating variants. We also recapitulated a significant burden of disruptive variants in genes and gene sets previously associated with other neurodevelopmental disorders. We present the first gene-based burden results from our exome meta-analysis, and extend the sample using an independent set of 4,000 whole-genome sequenced cases and 7,000 matched controls. Finally, we present a new exome association results browser that allows for easy viewing of identified variants and gene-based results. Discussion In summary, we introduce the largest multi-center effort to aggregate sequencing data of a psychiatric trait, and the initial results from the harmonization and analysis of over 65,000 exomes.

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