Abstract
| Original language | English |
|---|---|
| Article number | 100356 |
| Journal | Cell Genomics |
| Volume | 3 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 9 Aug 2023 |
Keywords
- ABCB11
- NRXN1
- genomics
- mosaicism
- schizophrenia
- somatic
- structural variants
- treatment resistance
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In: Cell Genomics, Vol. 3, No. 8, 100356, 09.08.2023.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions
AU - Maury, Eduardo A.
AU - Sherman, Maxwell A.
AU - Genovese, Giulio
AU - Gilgenast, Thomas G.
AU - Kamath, Tushar
AU - Burris, S. J.
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AU - Sullivan, Patrick
AU - Marshall, Christian R.
AU - Merico, Daniele
AU - Psychiatric Genomic Consortium Schizophrenia and CNV workgroup
AU - Thiruvahindrapuram, Bhooma
AU - Wang, Zhouzhi
AU - Scherer, Stephen W.
AU - Howrigan, Daniel P.
AU - Ripke, Stephan
AU - Bulik-Sullivan, Brendan
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AU - Antaki, Danny
AU - Shetty, Aniket
AU - Brain Somatic Mosaicism Network
AU - Gujral, Madhusudan
AU - Brandler, William M.
AU - Malhotra, Dheeraj
AU - Fuentes Fajarado, Karin V.
AU - Maile, Michelle S.
AU - Holmans, Peter A.
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AU - Nisenbaum, Laura
AU - Nordin, Annelie
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AU - O'Callaghan, Eadbhard
AU - Oh, Sang-Yun
AU - O'Neill, F. Anthony
AU - Paunio, Tiina
AU - Pietiläinen, Olli
AU - Perkins, Diana O.
AU - Quested, Digby
AU - Savitz, Adam
AU - Li, Qingqin S.
AU - Schwab, Sibylle G.
AU - Shi, Jianxin
AU - Spencer, Chris C. A.
AU - Thirumalai, Srinivas
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AU - Walsh, Dermot
AU - Wildenauer, Dieter B.
AU - Bramon, Elvira
AU - Darvasi, Ariel
AU - Posthuma, Danielle
AU - St. Clair, David
AU - Shanta, Omar
AU - Klein, Marieke
AU - Park, Peter J.
AU - Weinberger, Daniel
AU - Moran, John V.
AU - Gage, Fred H.
AU - Vaccarino, Flora M.
AU - Gleeson, Joseph
AU - Mathern, Gary
AU - Courchesne, Eric
AU - Roy, Subhojit
AU - Bizzotto, Sara
AU - Coulter, Michael
AU - Dias, Caroline
AU - D'Gama, Alissa
AU - Ganz, Javier
AU - Hill, Robert
AU - Huang, August Yue
AU - Khoshkhoo, Sattar
AU - Kim, Sonia
AU - Lodato, Michael
AU - Miller, Michael
AU - Borges-Monroy, Rebeca
AU - Rodin, Rachel
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 - Viswanadham, Vinay
AU - Jones, Attila
AU - Rosenbluh, Chaggai
AU - Cho, Sean
AU - Langmead, Ben
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 - Abyzov, Alexej
AU - Bae, Taejeong
AU - Jang, Yeongjun
AU - Wang, Yifan
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 - Amero, Aitor Serres
AU - Juan, David
AU - Lobon, Irene
AU - Marques-Bonet, Tomas
AU - Moruno, Manuel Solis
AU - Perez, Raquel Garcia
AU - Povolotskaya, Inna
AU - Soriano, Eduardo
AU - Averbuj, Dan
AU - Ball, Laurel
AU - Breuss, Martin
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 - Sun, Chen
AU - Zhao, Xuefang
AU - Zhou, Weichen
AU - Frisbie, Trenton J.
AU - Cherskov, Adriana
AU - Fasching, Liana
AU - Jourdon, Alexandre
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N1 - Funding Information: E.A.M. is supported by the Harvard/MIT MD-PhD program (T32GM007753), the Biomedical Informatics and Data Science Training Program (T15LM007092), and the Ruth L. Kirschstein NRSA F31 Fellowship (F31MH124292). G.G. is supported by NIH grant R01HG006855, NIH grant R01MH104964, and the Stanley Center for Psychiatric Research. S.A. was supported by NIH grant R01MH106056 and S.A. A.C. and C.A.W. were supported by the NIMH grant (U01MH106883) through the Brain Somatic Mosaicism Network (BSMN). C.A.W. is an investigator of the Howard Hughes Medical Institute. C.A.W. and E.A.L. are supported by the Allen Frontiers Program through the Allen Discovery Center for Human Brain Evolution. E.A.L. is supported by NIH grants (K01 AG051791, DP2 AG072437, and R01AG070921) and the SUHF foundation. J.S. is supported by NIH grants (MH113715, MH119746, MH109501, and MH119746). J.E.P.-C. and K.J.B. are supported by a Chan Zuckerberg Initiative grant (2020-221479). J.E.P.-C. is supported by NIH grants (DP1OD031253, R01NS-114226, R01MH12026, and U01DK127405). P.-R.L. is supported by NIH grant DP2 ES030554 and a Burroughs Wellcome Fund Career Award at the Scientific Interfaces. T.K. is supported by F30AG069446-01. E.Z.M. is supported by DP2AG058488, U01MH124602, and Chan Zuckerberg Initiative (no. 2017-175259). E.A.M. and C.A.W. conceived and designed the study. E.A.M. designed and implemented the statistical methods. E.A.M. performed computational analyses, with assistance from M.A.S. and G.G. J.S. curated the data and facilitated access. S.M. and A.C. facilitated acquisition of samples for whole-genome sequencing validation. J.T.R.W. M.O. and P.S. facilitated clinical and genomic data procurement for validation and interpretation. P.R. S.A. and K.J.B. generated the Hi-C data. T.G.G. and J.E.P.-C. analyzed and interpreted the Hi-C data. E.F. and K.J.B. generated and characterized the hiPSCs/neurons. T.K. S.B. and E.Z.M. contributed and analyzed the ABCB11 snRNA-seq data. E.A.L. P.-R.L. S.A.M. and J.S. provided comments and guidance throughout. E.A.M. E.A.L. and C.A.W. wrote the manuscript. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: E.A.M. is supported by the Harvard/MIT MD-PhD program ( T32GM007753 ), the Biomedical Informatics and Data Science Training Program ( T15LM007092 ), and the Ruth L. Kirschstein NRSA F31 Fellowship ( F31MH124292 ). G.G. is supported by NIH grant R01HG006855 , NIH grant R01MH104964 , and the Stanley Center for Psychiatric Research . S.A. was supported by NIH grant R01MH106056 and S.A., A.C., and C.A.W. were supported by the NIMH grant ( U01MH106883 ) through the Brain Somatic Mosaicism Network (BSMN). C.A.W. is an investigator of the Howard Hughes Medical Institute . C.A.W. and E.A.L. are supported by the Allen Frontiers Program through the Allen Discovery Center for Human Brain Evolution . E.A.L. is supported by NIH grants ( K01 AG051791 , DP2 AG072437 , and R01AG070921 ) and the SUHF foundation . J.S. is supported by NIH grants ( MH113715 , MH119746 , MH109501 , and MH119746 ). J.E.P.-C. and K.J.B. are supported by a Chan Zuckerberg Initiative grant ( 2020-221479 ). J.E.P.-C. is supported by NIH grants ( DP1OD031253 , R01NS-114226 , R01MH12026 , and U01DK127405 ). P.-R.L. is supported by NIH grant DP2 ES030554 and a Burroughs Wellcome Fund Career Award at the Scientific Interfaces . T.K. is supported by F30AG069446-01 . E.Z.M. is supported by DP2AG058488 , U01MH124602 , and Chan Zuckerberg Initiative (no. 2017-175259 ). Publisher Copyright: © 2023 The Author(s)
PY - 2023/8/9
Y1 - 2023/8/9
N2 - While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.
AB - While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.
KW - ABCB11
KW - NRXN1
KW - genomics
KW - mosaicism
KW - schizophrenia
KW - somatic
KW - structural variants
KW - treatment resistance
UR - https://www.scopus.com/pages/publications/85173227544
U2 - 10.1016/j.xgen.2023.100356
DO - 10.1016/j.xgen.2023.100356
M3 - Article
C2 - 37601975
SN - 2666-979X
VL - 3
JO - Cell Genomics
JF - Cell Genomics
IS - 8
M1 - 100356
ER -