Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Brain Somatic Mosaicism Network; Psychiatric Genomic Consortium Schizophrenia and CNV workgroup

doi:10.1016/j.xgen.2023.100356

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Brain Somatic Mosaicism Network, Psychiatric Genomic Consortium Schizophrenia and CNV workgroup

Division of Adult Acute Clinical

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

7 Scopus citations

Abstract

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.

Original language	English
Article number	100356
Journal	Cell Genomics
Volume	3
Issue number	8
DOIs	https://doi.org/10.1016/j.xgen.2023.100356
State	Published - Aug 9 2023

Keywords

ABCB11
NRXN1
genomics
mosaicism
schizophrenia
somatic
structural variants
treatment resistance

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10.1016/j.xgen.2023.100356

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@article{763f7f5494b34bc5b44d2640b1efa4c0,

title = "Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions",

abstract = "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.",

keywords = "ABCB11, NRXN1, genomics, mosaicism, schizophrenia, somatic, structural variants, treatment resistance",

author = "{Brain Somatic Mosaicism Network} and {Psychiatric Genomic Consortium Schizophrenia and CNV workgroup} and Maury, {Eduardo A.} and Sherman, {Maxwell A.} and Giulio Genovese and Gilgenast, {Thomas G.} and Tushar Kamath and Burris, {S. J.} and Prashanth Rajarajan and Erin Flaherty and Schahram Akbarian and Andrew Chess and McCarroll, {Steven A.} and Loh, {Po Ru} and Phillips-Cremins, {Jennifer E.} and Brennand, {Kristen J.} and Macosko, {Evan Z.} and Walters, {James T.R.} and Michael O'Donovan and Patrick Sullivan and Marshall, {Christian R.} and Daniele Merico and Bhooma Thiruvahindrapuram and Zhouzhi Wang and Scherer, {Stephen W.} and Howrigan, {Daniel P.} and Stephan Ripke and Brendan Bulik-Sullivan and Farh, {Kai How} and Menachem Fromer and Goldstein, {Jacqueline I.} and Hailiang Huang and Phil Lee and Daly, {Mark J.} and Neale, {Benjamin M.} and Belliveau, {Richard A.} and Bergen, {Sarah E.} and Elizabeth Bevilacqua and Chambert, {Kimberley D.} and Colm O'Dushlaine and Scolnick, {Edward M.} and Smoller, {Jordan W.} and Moran, {Jennifer L.} and Aarno Palotie and Petryshen, {Tracey L.} and Wenting Wu and Greer, {Douglas S.} and Danny Antaki and Aniket Shetty and Madhusudan Gujral and Brandler, {William M.} and Dheeraj Malhotra and {Fuentes Fajarado}, {Karin V.} and Maile, {Michelle S.} and Holmans, {Peter A.} and Noa Carrera and Nick Craddock and Valentina Escott-Price and Lyudmila Georgieva and Hamshere, {Marian L.} and David Kavanagh and Legge, {Sophie E.} and Pocklington, {Andrew J.} and Richards, {Alexander L.} and Ruderfer, {Douglas M.} and Williams, {Nigel M.} and George Kirov and Owen, {Michael J.} and Dalila Pinto and Guiqing Cai and Davis, {Kenneth L.} and Elodie Drapeau and Friedman, {Joseph I.} and Vahram Haroutunian and Elena Parkhomenko and Abraham Reichenberg and Silverman, {Jeremy M.} and Buxbaum, {Joseph D.} and Enrico Domenici and Ingrid Agartz and Srdjan Djurovic and Morten Mattingsdal and Ingrid Melle and Andreassen, {Ole A.} and J{\"o}nsson, {Erik G.} and Erik S{\"o}derman and Margot Albus and Madeline Alexander and Claudine Laurent and Levinson, {Douglas F.} and Farooq Amin and Joshua Atkins and Cairns, {Murray J.} and Scott, {Rodney J.} and Tooney, {Paul A.} and Wu, {Jing Qin} and Bacanu, {Silviu A.} and Bigdeli, {Tim B.} and Reimers, {Mark A.} and Webb, {Bradley T.} and Wolen, {Aaron R.} and Wormley, {Brandon K.} and Kendler, {Kenneth S.} and Riley, {Brien P.} and K{\"a}hler, {Anna K.} and Magnusson, {Patrik K.E.} and Hultman, {Christina M.} and Marcelo Bertalan and Thomas Hansen and Line Olsen and Rasmussen, {Henrik B.} and Thomas Werge and Manuel Mattheisen and Black, {Donald W.} and Richard Bruggeman and Buccola, {Nancy G.} and Buckner, {Randy L.} and Roffman, {Joshua L.} and William Byerley and Wiepke Cahn and Kahn, {Ren{\'e} S.} and Eric Strengman and Ophoff, {Roel A.} and Carr, {Vaughan J.} and Catts, {Stanley V.} and Henskens, {Frans A.} and Loughland, {Carmel M.} and Michie, {Patricia T.} and Christos Pantelis and Ulrich Schall and Jablensky, {Assen V.} and Kelly, {Brian J.} and Dominique Campion and Cantor, {Rita M.} and Wei Cheng and Cloninger, {C. Robert} and Svrakic, {Dragan M.} and David Cohen and Paul Cormican and Gary Donohoe and Morris, {Derek W.} and Aiden Corvin and Michael Gill and Benedicto Crespo-Facorro and Crowley, {James J.} and Farrell, {Martilias S.} and Paola Giusti-Rodr{\'i}guez and Yunjung Kim and Szatkiewicz, {Jin P.} and Stephanie Williams and David Curtis and Jonathan Pimm and Hugh Gurling and Andrew McQuillin and Michael Davidson and Mark Weiser and Franziska Degenhardt and Forstner, {Andreas J.} and Stefan Herms and Per Hoffmann and Andrea Hofman and Sven Cichon and N{\"o}then, {Markus M.} and {Del Favero}, Jurgen and DeLisi, {Lynn E.} and McCarley, {Robert W.} and Levy, {Deborah L.} and Mesholam-Gately, {Raquelle I.} and Seidman, {Larry J.} and Dimitris Dikeos and Papadimitriou, {George N.} and Timothy Dinan and Jubao Duan and Sanders, {Alan R.} and Gejman, {Pablo V.} and Gershon, {Elliot S.} and Frank Dudbridge and Peter Eichhammer and Johan Eriksson and Veikko Salomaa and Laurent Essioux and Fanous, {Ayman H.} and Knowles, {James A.} and Pato, {Michele T.} and Pato, {Carlos N.} and Josef Frank and Sandra Meier and Schulze, {Thomas G.} and Jana Strohmaier and Witt, {Stephanie H.} and Marcella Rietschel and Lude Franke and Juha Karjalainen and Robert Freedman and Ann Olincy and Freimer, {Nelson B.} and Purcell, {Shaun M.} and Panos Roussos and Stahl, {Eli A.} and Pamela Sklar and Ina Giegling and Hartmann, {Annette M.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = aug,

day = "9",

doi = "10.1016/j.xgen.2023.100356",

language = "English",

volume = "3",

journal = "Cell Genomics",

issn = "2666-979X",

number = "8",

}

TY - JOUR

T1 - Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

AU - Brain Somatic Mosaicism Network

AU - Psychiatric Genomic Consortium Schizophrenia and CNV workgroup

AU - Maury, Eduardo A.

AU - Sherman, Maxwell A.

AU - Genovese, Giulio

AU - Gilgenast, Thomas G.

AU - Kamath, Tushar

AU - Burris, S. J.

AU - Rajarajan, Prashanth

AU - Flaherty, Erin

AU - Akbarian, Schahram

AU - Chess, Andrew

AU - McCarroll, Steven A.

AU - Loh, Po Ru

AU - Phillips-Cremins, Jennifer E.

AU - Brennand, Kristen J.

AU - Macosko, Evan Z.

AU - Walters, James T.R.

AU - O'Donovan, Michael

AU - Sullivan, Patrick

AU - Marshall, Christian R.

AU - Merico, Daniele

AU - Thiruvahindrapuram, Bhooma

AU - Wang, Zhouzhi

AU - Scherer, Stephen W.

AU - Howrigan, Daniel P.

AU - Ripke, Stephan

AU - Bulik-Sullivan, Brendan

AU - Farh, Kai How

AU - Fromer, Menachem

AU - Goldstein, Jacqueline I.

AU - Huang, Hailiang

AU - Lee, Phil

AU - Daly, Mark J.

AU - Neale, Benjamin M.

AU - Belliveau, Richard A.

AU - Bergen, Sarah E.

AU - Bevilacqua, Elizabeth

AU - Chambert, Kimberley D.

AU - O'Dushlaine, Colm

AU - Scolnick, Edward M.

AU - Smoller, Jordan W.

AU - Moran, Jennifer L.

AU - Palotie, Aarno

AU - Petryshen, Tracey L.

AU - Wu, Wenting

AU - Greer, Douglas S.

AU - Antaki, Danny

AU - Shetty, Aniket

AU - Gujral, Madhusudan

AU - Brandler, William M.

AU - Malhotra, Dheeraj

AU - Fuentes Fajarado, Karin V.

AU - Maile, Michelle S.

AU - Holmans, Peter A.

AU - Carrera, Noa

AU - Craddock, Nick

AU - Escott-Price, Valentina

AU - Georgieva, Lyudmila

AU - Hamshere, Marian L.

AU - Kavanagh, David

AU - Legge, Sophie E.

AU - Pocklington, Andrew J.

AU - Richards, Alexander L.

AU - Ruderfer, Douglas M.

AU - Williams, Nigel M.

AU - Kirov, George

AU - Owen, Michael J.

AU - Pinto, Dalila

AU - Cai, Guiqing

AU - Davis, Kenneth L.

AU - Drapeau, Elodie

AU - Friedman, Joseph I.

AU - Haroutunian, Vahram

AU - Parkhomenko, Elena

AU - Reichenberg, Abraham

AU - Silverman, Jeremy M.

AU - Buxbaum, Joseph D.

AU - Domenici, Enrico

AU - Agartz, Ingrid

AU - Djurovic, Srdjan

AU - Mattingsdal, Morten

AU - Melle, Ingrid

AU - Andreassen, Ole A.

AU - Jönsson, Erik G.

AU - Söderman, Erik

AU - Albus, Margot

AU - Alexander, Madeline

AU - Laurent, Claudine

AU - Levinson, Douglas F.

AU - Amin, Farooq

AU - Atkins, Joshua

AU - Cairns, Murray J.

AU - Scott, Rodney J.

AU - Tooney, Paul A.

AU - Wu, Jing Qin

AU - Bacanu, Silviu A.

AU - Bigdeli, Tim B.

AU - Reimers, Mark A.

AU - Webb, Bradley T.

AU - Wolen, Aaron R.

AU - Wormley, Brandon K.

AU - Kendler, Kenneth S.

AU - Riley, Brien P.

AU - Kähler, Anna K.

AU - Magnusson, Patrik K.E.

AU - Hultman, Christina M.

AU - Bertalan, Marcelo

AU - Hansen, Thomas

AU - Olsen, Line

AU - Rasmussen, Henrik B.

AU - Werge, Thomas

AU - Mattheisen, Manuel

AU - Black, Donald W.

AU - Bruggeman, Richard

AU - Buccola, Nancy G.

AU - Buckner, Randy L.

AU - Roffman, Joshua L.

AU - Byerley, William

AU - Cahn, Wiepke

AU - Kahn, René S.

AU - Strengman, Eric

AU - Ophoff, Roel A.

AU - Carr, Vaughan J.

AU - Catts, Stanley V.

AU - Henskens, Frans A.

AU - Loughland, Carmel M.

AU - Michie, Patricia T.

AU - Pantelis, Christos

AU - Schall, Ulrich

AU - Jablensky, Assen V.

AU - Kelly, Brian J.

AU - Campion, Dominique

AU - Cantor, Rita M.

AU - Cheng, Wei

AU - Cloninger, C. Robert

AU - Svrakic, Dragan M.

AU - Cohen, David

AU - Cormican, Paul

AU - Donohoe, Gary

AU - Morris, Derek W.

AU - Corvin, Aiden

AU - Gill, Michael

AU - Crespo-Facorro, Benedicto

AU - Crowley, James J.

AU - Farrell, Martilias S.

AU - Giusti-Rodríguez, Paola

AU - Kim, Yunjung

AU - Szatkiewicz, Jin P.

AU - Williams, Stephanie

AU - Curtis, David

AU - Pimm, Jonathan

AU - Gurling, Hugh

AU - McQuillin, Andrew

AU - Davidson, Michael

AU - Weiser, Mark

AU - Degenhardt, Franziska

AU - Forstner, Andreas J.

AU - Herms, Stefan

AU - Hoffmann, Per

AU - Hofman, Andrea

AU - Cichon, Sven

AU - Nöthen, Markus M.

AU - Del Favero, Jurgen

AU - DeLisi, Lynn E.

AU - McCarley, Robert W.

AU - Levy, Deborah L.

AU - Mesholam-Gately, Raquelle I.

AU - Seidman, Larry J.

AU - Dikeos, Dimitris

AU - Papadimitriou, George N.

AU - Dinan, Timothy

AU - Duan, Jubao

AU - Sanders, Alan R.

AU - Gejman, Pablo V.

AU - Gershon, Elliot S.

AU - Dudbridge, Frank

AU - Eichhammer, Peter

AU - Eriksson, Johan

AU - Salomaa, Veikko

AU - Essioux, Laurent

AU - Fanous, Ayman H.

AU - Knowles, James A.

AU - Pato, Michele T.

AU - Pato, Carlos N.

AU - Frank, Josef

AU - Meier, Sandra

AU - Schulze, Thomas G.

AU - Strohmaier, Jana

AU - Witt, Stephanie H.

AU - Rietschel, Marcella

AU - Franke, Lude

AU - Karjalainen, Juha

AU - Freedman, Robert

AU - Olincy, Ann

AU - Freimer, Nelson B.

AU - Purcell, Shaun M.

AU - Roussos, Panos

AU - Stahl, Eli A.

AU - Sklar, Pamela

AU - Giegling, Ina

AU - Hartmann, Annette M.

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 - http://www.scopus.com/inward/record.url?scp=85173227544&partnerID=8YFLogxK

U2 - 10.1016/j.xgen.2023.100356

DO - 10.1016/j.xgen.2023.100356

M3 - Article

C2 - 37601975

AN - SCOPUS:85173227544

SN - 2666-979X

VL - 3

JO - Cell Genomics

JF - Cell Genomics

IS - 8

M1 - 100356

ER -

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

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