Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes
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.
Authors
- Christopher A. Walsh (ORCID: https://orcid.org/0000-0002-0156-2238)
- Sanan Venkatesh (ORCID: https://orcid.org/0000-0002-3094-2731)
- Elise Root (ORCID: https://orcid.org/0009-0000-8158-6442)
- Peter J. Park (ORCID: https://orcid.org/0000-0001-9378-960X)
- Attila Jones (ORCID: https://orcid.org/0000-0003-0257-8781)
- Schahram Akbarian (ORCID: https://orcid.org/0000-0001-7700-0891)
- Chaggai Rosenbluh (ORCID: https://orcid.org/0000-0003-3329-1396)
- Andrew Chess (ORCID: https://orcid.org/0000-0002-4501-8816)
- Georgios Voloudakis (ORCID: https://orcid.org/0000-0002-5729-632X)
- Thanh Thanh L. Nguyen (ORCID: https://orcid.org/0000-0002-2281-6540)
- Eunjung Alice Lee (ORCID: https://orcid.org/0000-0002-6574-9261)
- Eduardo A. Maury (ORCID: https://orcid.org/0000-0002-2211-8611)
- Sattar Khoshkhoo (ORCID: https://orcid.org/0000-0003-3348-557X)
- Shamil Sunyaev (ORCID: https://orcid.org/0000-0001-5715-5677)
- Steven K. Reilly (ORCID: https://orcid.org/0000-0003-3140-1483)
- Kristen Brennand (ORCID: https://orcid.org/0000-0003-0993-5956)
- Alexej Abyzov (ORCID: https://orcid.org/0000-0001-5405-6729)
- Yasmine Chahine
- Vladimir B. Seplyarskiy (ORCID: https://orcid.org/0000-0003-3161-8770)
- Yifan Wang (ORCID: https://orcid.org/0000-0001-8056-9755)
- Sijing Zhao (ORCID: https://orcid.org/0000-0003-1247-6834)
- Taejong Bae
- Panagiotis Roussos
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Allen Institute for Brain Science (US)
- Mayo Clinic (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Yale University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science
- Published
- 2024-10-10
- DOI
- https://doi.org/10.1126/science.adq1456
- Citations
- 17
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 3.97
Funders
- John Templeton Foundation
- University of Pittsburgh
- National Institutes of Health
- National Institute of Mental Health