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Schizophrenia (SCZ) is a complex neuropsychiatric disorder in which both germline genetic mutations and environmental factors have been implicated. During development, cells accumulate somatic, mosaic mutations in ways shaped by the cellular environment or endogenous processes, but these early developmental mutational patterns have not been studied in SCZ. Here we analyzed deep (239x) whole-genome sequencing (WGS) of DNA from neurons isolated from 61 SCZ and 25 control postmortem brains to capture mutations occurring before or during fetal neurogenesis. While there was no significant difference in the genome-wide rate of somatic mutations in SCZ compared to controls, there was an enrichment of somatic variants in open chromatin regions in cases compared to controls (p <0.0001). Specifically, mosaic CpG transversions (CpG>GpG) and T>G mutations were highly enriched at transcription factor binding sites (TFBS) overlapping open-chromatin regions in SCZ. This enrichment was not seen in controls. High-throughput functional experiments indicated that a subset of variants originating from these mutational processes alter downstream gene expression, affecting known SCZ risk genes as well as genes involved in neurodevelopment. While the relationship of these mutational processes with SCZ can reflect difference in factors not causally involved in disease. Increased somatic mutational burden at TFBS active in fetal brain is well-positioned to create gene dysregulation in concert with germline risk alleles in SCZ and potentially contribute to liability.

The methods for each analysis is outlined in the Supplmentary Materials and methods section of the manuscript. The notebooks folder contains R code to recreate the analyses of each of the main figures.