Citations 2
Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes
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 , Network‡, Brain Somatic Mosaicism, Brennand, Kristen , Reilly, Steven K. , Sunyaev, Shamil , Chess, Andrew , Bae, Taejeong , Moran, John V. , Zhou, Weichen , Zhu, Xiaowei , Bizzotto, Sara , Galor, Alon , Yang, Xiaoxu , Bae, Taejeong , Park, Peter J , Akbarian, Schahram , Brennand, Kristen , Reilly, Steven , Lee, Eunjung A , Sunyaev, Shamil R , Walsh, Christopher A , Chess, Andrew , Nguyen, Thanh Thanh L. , Abyzov, Alexej , Wang, Yifan , Voloudakis, Georgios , Maury, Eduardo A. , Jones, Attila , Seplyarskiy, Vladimir , Root, Elise , Network‡, Brain Somatic Mosaicism, Park, Peter J. , Akbarian, Schahram , Walsh, Christopher A.
Science | October 10, 2024 | Volume: 386 | Issue: 6718 | Pages: 217-224
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.
Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder.
McCarthy, Michael J. , Mishra, Himanshu , Wei, Heather, Rohr, Kayla E., Maihofer, Adam X. , Ko, Insu, Shilling, Paul D. , Berrettini, Wade H. , Brennand, Kristen , Calabrese, Joseph R. , Frye, Mark A. , Øedegaard, Ketil J. , Zandi, Peter P. , McCarthy, Michael , Shilling, Paul , Brennand, Kristen , Mishra, Himanshu, Nievergelt, Caroline M , Alda, Martin , Coryell, William , Gage, Fred H , Gershon, Elliot S. , McInnis, Melvin G. , Nurnberger, John I , Kelsoe, John R
No container title available | September 7, 2022 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.