Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes

• Published in: Science (American Association for the Advancement of Science) Vol. 386; no. 6718; pp. 217 - 224
• Main Authors: Maury, Eduardo A, Jones, Attila, Seplyarskiy, Vladimir, Nguyen, Thanh Thanh L, Rosenbluh, Chaggai, Bae, Taejong, Wang, Yifan, Abyzov, Alexej, Khoshkhoo, Sattar, Chahine, Yasmine, Zhao, Sijing, Venkatesh, Sanan, Root, Elise, Voloudakis, Georgios, Roussos, Panagiotis, Park, Peter J, Akbarian, Schahram, Brennand, Kristen, Reilly, Steven, Lee, Eunjung A, Sunyaev, Shamil R, Walsh, Christopher A, Chess, Andrew
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 11.10.2024
• Subjects: Binding Sites; Brain - embryology; Brain - metabolism; Case-Control Studies; Chromatin - metabolism; CpG Islands; Female; Gene sequencing; Humans; Male; Mental disorders; Mosaicism; Mutation; Neurodevelopmental disorders; Neurogenesis; Neurogenesis - genetics; Neurological diseases; Neurons - metabolism; Nucleotides; Prefrontal cortex; Schizophrenia; Schizophrenia - genetics; Transcription Factors - genetics; Transcription Factors - metabolism; Whole Genome Sequencing
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adq1456

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.