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 - Abyzov, Alexej
N1 - 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 - http://www.scopus.com/inward/record.url?scp=85173227544&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85173227544&partnerID=8YFLogxK
U2 - 10.1016/j.xgen.2023.100356
DO - 10.1016/j.xgen.2023.100356
M3 - Article
AN - SCOPUS:85173227544
SN - 2666-979X
VL - 3
JO - Cell Genomics
JF - Cell Genomics
IS - 8
M1 - 100356
ER -