Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes

• 成果类型: Article
• 署名作者: 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
• 署名单位: Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Yale University; Yale University; Mayo Clinic; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10955
• DOI: 10.1126/science.adq1456
• 发表日期: 2024-10-01
• 页码: 217-224
• 关键词: genome-wide association; cerebral-cortex; binding sites; variants; disorder; origin; FAMILY; repair; foxo3; RISK

摘要

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 (239x) 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.