Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes

Eduardo A. Maury; Attila Jones; Vladimir Seplyarskiy; Thanh Thanh L. Nguyen; Chaggai Rosenbluh; Taejeong Bae; Yifan Wang; Alexej Abyzov; Sattar Khoshkhoo; Yasmine Chahine; Sijing Zhao; Sanan Venkatesh; Elise Root; Georgios Voloudakis; Panagiotis Roussos; Brain Somatic Mosaicism Network; Jennifer Erwin; Peter J. Park; Schahram Akbarian; Kristen Brennand; Steven Reilly; Eunjung A. Lee

doi:10.1126/science.adq1456

Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes

Eduardo A. Maury, Attila Jones, Vladimir Seplyarskiy, Thanh Thanh L. Nguyen, Chaggai Rosenbluh, Taejeong Bae, Yifan Wang, Alexej Abyzov, Sattar Khoshkhoo, Yasmine Chahine, Sijing Zhao, Sanan Venkatesh, Elise Root, Georgios Voloudakis, Panagiotis Roussos, Brain Somatic Mosaicism Network, Jennifer Erwin, Peter J. Park, Schahram Akbarian, Kristen BrennandSteven Reilly, Eunjung A. Lee

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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.

Original language	English
Pages (from-to)	217-224
Number of pages	8
Journal	Science
Volume	386
Issue number	6718
DOIs	https://doi.org/10.1126/science.adq1456
Publication status	Published - 11 Oct 2024
Externally published	Yes

Keywords

Somatic mosaicism
schizophrenia
germline mutations
whole genome sequencing
Transcription factor binding

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Maury, E. A., Jones, A., Seplyarskiy, V., Nguyen, T. T. L., Rosenbluh, C., Bae, T., Wang, Y., Abyzov, A., Khoshkhoo, S., Chahine, Y., Zhao, S., Venkatesh, S., Root, E., Voloudakis, G., Roussos, P., Brain Somatic Mosaicism Network, Erwin, J., Park, P. J., Akbarian, S., ... Lee, E. A. (2024). Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes. Science, 386(6718), 217-224. https://doi.org/10.1126/science.adq1456

@article{277e143bfee64d19ada1e3ccc1768ba7,

title = "Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes",

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.",

keywords = "Somatic mosaicism, schizophrenia, germline mutations, whole genome sequencing, Transcription factor binding",

author = "Maury, {Eduardo A.} and Attila Jones and Vladimir Seplyarskiy and Nguyen, {Thanh Thanh L.} and Chaggai Rosenbluh and Taejeong Bae and Yifan Wang and Alexej Abyzov and Sattar Khoshkhoo and Yasmine Chahine and Sijing Zhao and Sanan Venkatesh and Elise Root and Georgios Voloudakis and Panagiotis Roussos and {Brain Somatic Mosaicism Network} and Sara Bizzotto and Michael Coulter and Caroline Dias and Alissa D'Gama and Javier Ganz and Robert Hill and Huang, {August Yue} and Sonia Kim and Alice Lee and Michael Lodato and Michael Miller and Rebeca Borges-Monroy and Rachel Rodin and Walsh, {Christopher A.} and Zinan Zhou and Craig Bohrson and Chong Chu and Isidro Cortes-Ciriano and Yanmei Dou and Alon Galor and Doga Gulhan and Minseok Kwon and Joe Luquette and Maxwell Sherman and Vinay Viswanadham and Andrew Chess and Sean Cho and Ben Langmead and Jonathan Pevsner and Jeremy Thorpe and Jennifer Erwin and Andrew Jaffe and Michael McConnell and Rujuta Narurkar and Apua Paquola and Jooheon Shin and Richard Straub and Daniel Weinberger and Yeongjun Jang and Cindy Molitor and Mette Peters and Sunyaev, {Shamil R.} and Fred Gage and Sara Linker and Patrick Reed and Meiyan Wang and Alexander Urban and Bo Zhou and Xiaowei Zhu and Reenal Pattni and {Serres Amero}, Aitor and David Juan and Irene Lobon and Tomas Marques-Bonet and {Solis Moruno}, Manuel and {Garcia Perez}, Raquel and Inna Povolotskaya and Eduardo Soriano and Gary Mathern and Danny Antaki and Dan Averbuj and Laurel Ball and Martin Breuss and Eric Courchesne and Joseph Gleeson and Xiaoxu Yang and Changuk Chung and Emery, {Sarah B.} and Flasch, {Diane A.} and Kidd, {Jeffrey M.} and Kopera, {Huira C.} and Kwan, {Kenneth Y.} and Mills, {Ryan E.} and Moldovan, {John B.} and Moran, {John V.} and Chen Sun and Xuefang Zhao and Weichen Zhou and Frisbie, {Trenton J.} and Adriana Cherskov and Liana Fasching and Alexandre Jourdon and Sirisha Pochareddy and Soraya Scuderi and Nenad Sestan and Flora Vaccarino and Park, {Peter J.} and Schahram Akbarian and Kristen Brennand and Steven Reilly and Lee, {Eunjung A.}",

year = "2024",

month = oct,

day = "11",

doi = "10.1126/science.adq1456",

language = "English",

volume = "386",

pages = "217--224",

journal = "Science",

issn = "0036-8075",

publisher = "PubMed",

number = "6718",

}

Maury, EA, Jones, A, Seplyarskiy, V, Nguyen, TTL, Rosenbluh, C, Bae, T, Wang, Y, Abyzov, A, Khoshkhoo, S, Chahine, Y, Zhao, S, Venkatesh, S, Root, E, Voloudakis, G, Roussos, P, Brain Somatic Mosaicism Network, Erwin, J, Park, PJ, Akbarian, S, Brennand, K, Reilly, S & Lee, EA 2024, 'Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes', Science, vol. 386, no. 6718, pp. 217-224. https://doi.org/10.1126/science.adq1456

TY - JOUR

T1 - Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes

AU - Maury, Eduardo A.

AU - Jones, Attila

AU - Seplyarskiy, Vladimir

AU - Nguyen, Thanh Thanh L.

AU - Rosenbluh, Chaggai

AU - Bae, Taejeong

AU - Wang, Yifan

AU - Abyzov, Alexej

AU - Khoshkhoo, Sattar

AU - Chahine, Yasmine

AU - Zhao, Sijing

AU - Venkatesh, Sanan

AU - Root, Elise

AU - Voloudakis, Georgios

AU - Roussos, Panagiotis

AU - Brain Somatic Mosaicism Network

AU - Bizzotto, Sara

AU - Coulter, Michael

AU - Dias, Caroline

AU - D'Gama, Alissa

AU - Ganz, Javier

AU - Hill, Robert

AU - Huang, August Yue

AU - Kim, Sonia

AU - Lee, Alice

AU - Lodato, Michael

AU - Miller, Michael

AU - Borges-Monroy, Rebeca

AU - Rodin, Rachel

AU - Walsh, Christopher A.

AU - Zhou, Zinan

AU - Bohrson, Craig

AU - Chu, Chong

AU - Cortes-Ciriano, Isidro

AU - Dou, Yanmei

AU - Galor, Alon

AU - Gulhan, Doga

AU - Kwon, Minseok

AU - Luquette, Joe

AU - Sherman, Maxwell

AU - Viswanadham, Vinay

AU - Chess, Andrew

AU - Cho, Sean

AU - Langmead, Ben

AU - Pevsner, Jonathan

AU - Thorpe, Jeremy

AU - Erwin, Jennifer

AU - Jaffe, Andrew

AU - McConnell, Michael

AU - Narurkar, Rujuta

AU - Paquola, Apua

AU - Shin, Jooheon

AU - Straub, Richard

AU - Weinberger, Daniel

AU - Jang, Yeongjun

AU - Molitor, Cindy

AU - Peters, Mette

AU - Sunyaev, Shamil R.

AU - Gage, Fred

AU - Linker, Sara

AU - Reed, Patrick

AU - Wang, Meiyan

AU - Urban, Alexander

AU - Zhou, Bo

AU - Zhu, Xiaowei

AU - Pattni, Reenal

AU - Serres Amero, Aitor

AU - Juan, David

AU - Lobon, Irene

AU - Marques-Bonet, Tomas

AU - Solis Moruno, Manuel

AU - Garcia Perez, Raquel

AU - Povolotskaya, Inna

AU - Soriano, Eduardo

AU - Mathern, Gary

AU - Antaki, Danny

AU - Averbuj, Dan

AU - Ball, Laurel

AU - Breuss, Martin

AU - Courchesne, Eric

AU - Gleeson, Joseph

AU - Yang, Xiaoxu

AU - Chung, Changuk

AU - Emery, Sarah B.

AU - Flasch, Diane A.

AU - Kidd, Jeffrey M.

AU - Kopera, Huira C.

AU - Kwan, Kenneth Y.

AU - Mills, Ryan E.

AU - Moldovan, John B.

AU - Moran, John V.

AU - Sun, Chen

AU - Zhao, Xuefang

AU - Zhou, Weichen

AU - Frisbie, Trenton J.

AU - Cherskov, Adriana

AU - Fasching, Liana

AU - Jourdon, Alexandre

AU - Pochareddy, Sirisha

AU - Scuderi, Soraya

AU - Sestan, Nenad

AU - Vaccarino, Flora

AU - Park, Peter J.

AU - Akbarian, Schahram

AU - Brennand, Kristen

AU - Reilly, Steven

AU - Lee, Eunjung A.

PY - 2024/10/11

Y1 - 2024/10/11

N2 - 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.

AB - 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.

KW - Somatic mosaicism

KW - schizophrenia

KW - germline mutations

KW - whole genome sequencing

KW - Transcription factor binding

UR - http://www.scopus.com/inward/record.url?scp=85206024035&partnerID=8YFLogxK

U2 - 10.1126/science.adq1456

DO - 10.1126/science.adq1456

M3 - Article

C2 - 39388546

AN - SCOPUS:85206024035

SN - 0036-8075

VL - 386

SP - 217

EP - 224

JO - Science

JF - Science

IS - 6718

ER -

Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes

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Keywords

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