Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes
Eduardo A. Maury, Attila Jones, Vladimir B. Seplyarskiy, Thanh Thanh L. Nguyen, Chaggai Rosenbluh, Taejong Bae, Yifan Wang, Alexej Abyzov, Sattar Khoshkhoo, Yasmine Chahine, Sijing Zhao, Sanan Venkatesh, Elise Root, Georgios Voloudakis, Panagiotis Roussos, Elise Root, Peter J. Park, Schahram Akbarian, Kristen Brennand, Steven K. Reilly, Eunjung Alice Lee, Shamil Sunyaev, Christopher A. Walsh, Andrew Chess, Shamil Sunyaev, Christopher A. Walsh, Andrew Chess
Abstract
Germline mutations modulate the risk of developing schizophrenia (SCZ). Much less is known about the role of mosaic somatic mutations in the context of SCZ. Deep (239×) whole-genome sequencing (WGS) of brain neurons from 61 SCZ cases and 25 controls postmortem identified mutations occurring during prenatal neurogenesis. SCZ cases showed increased somatic variants in open chromatin, with increased mosaic CpG transversions (CpG>GpG) and T>G mutations at transcription factor binding sites (TFBSs) overlapping open chromatin, a result not seen in controls. Some of these variants alter gene expression, including SCZ risk genes and genes involved in neurodevelopment. Although these mutational processes can reflect a difference in factors indirectly involved in disease, increased somatic mutations at developmental TFBSs could also potentially contribute to SCZ.