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

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Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions. / Maury, Eduardo A.; Sherman, Maxwell A.; Genovese, Giulio; Gilgenast, Thomas G.; Kamath, Tushar; Burris, S. J.; Rajarajan, Prashanth; Flaherty, Erin; Akbarian, Schahram; Chess, Andrew; McCarroll, Steven A.; Loh, Po Ru; Phillips-Cremins, Jennifer E.; Brennand, Kristen J.; Macosko, Evan Z.; Walters, James T.R.; O'Donovan, Michael; Sullivan, Patrick; Werge, Thomas (Member of author collaboration); Pers, Tune H. (Member of author collaboration); Brain Somatic Mosaicism Network; Psychiatric Genomic Consortium Schizophrenia and CNV workgroup.

In: Cell Genomics, Vol. 3, No. 8, 100356, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Maury, EA, Sherman, MA, Genovese, G, Gilgenast, TG, Kamath, T, Burris, SJ, Rajarajan, P, Flaherty, E, Akbarian, S, Chess, A, McCarroll, SA, Loh, PR, Phillips-Cremins, JE, Brennand, KJ, Macosko, EZ, Walters, JTR, O'Donovan, M, Sullivan, P, Werge, T, Pers, TH, Brain Somatic Mosaicism Network & Psychiatric Genomic Consortium Schizophrenia and CNV workgroup 2023, 'Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions', Cell Genomics, vol. 3, no. 8, 100356. https://doi.org/10.1016/j.xgen.2023.100356

APA

Maury, E. A., Sherman, M. A., Genovese, G., Gilgenast, T. G., Kamath, T., Burris, S. J., Rajarajan, P., Flaherty, E., Akbarian, S., Chess, A., McCarroll, S. A., Loh, P. R., Phillips-Cremins, J. E., Brennand, K. J., Macosko, E. Z., Walters, J. T. R., O'Donovan, M., Sullivan, P., Werge, T., ... Psychiatric Genomic Consortium Schizophrenia and CNV workgroup (2023). Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions. Cell Genomics, 3(8), [100356]. https://doi.org/10.1016/j.xgen.2023.100356

Vancouver

Maury EA, Sherman MA, Genovese G, Gilgenast TG, Kamath T, Burris SJ et al. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions. Cell Genomics. 2023;3(8). 100356. https://doi.org/10.1016/j.xgen.2023.100356

Author

Maury, Eduardo A. ; Sherman, Maxwell A. ; Genovese, Giulio ; Gilgenast, Thomas G. ; Kamath, Tushar ; Burris, S. J. ; Rajarajan, Prashanth ; Flaherty, Erin ; Akbarian, Schahram ; Chess, Andrew ; McCarroll, Steven A. ; Loh, Po Ru ; Phillips-Cremins, Jennifer E. ; Brennand, Kristen J. ; Macosko, Evan Z. ; Walters, James T.R. ; O'Donovan, Michael ; Sullivan, Patrick ; Werge, Thomas ; Pers, Tune H. ; Brain Somatic Mosaicism Network ; Psychiatric Genomic Consortium Schizophrenia and CNV workgroup. / Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions. In: Cell Genomics. 2023 ; Vol. 3, No. 8.

Bibtex

@article{49c7e6dbd3a34333826babbaed7339b9,
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, genomics, mosaicism, NRXN1, schizophrenia, somatic, structural variants, treatment resistance",
author = "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 Thomas Werge and Pers, {Tune H.} and {Brain Somatic Mosaicism Network} and {Psychiatric Genomic Consortium Schizophrenia and CNV workgroup}",
note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
doi = "10.1016/j.xgen.2023.100356",
language = "English",
volume = "3",
journal = "Cell Genomics",
issn = "2666-979x",
publisher = "Elsevier",
number = "8",

}

RIS

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.

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 - Brain Somatic Mosaicism Network

AU - Psychiatric Genomic Consortium Schizophrenia and CNV workgroup

A2 - Werge, Thomas

A2 - Pers, Tune H.

N1 - Publisher Copyright: © 2023 The Author(s)

PY - 2023

Y1 - 2023

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 - genomics

KW - mosaicism

KW - NRXN1

KW - schizophrenia

KW - somatic

KW - structural variants

KW - treatment resistance

U2 - 10.1016/j.xgen.2023.100356

DO - 10.1016/j.xgen.2023.100356

M3 - Journal article

C2 - 37601975

AN - SCOPUS:85173227544

VL - 3

JO - Cell Genomics

JF - Cell Genomics

SN - 2666-979x

IS - 8

M1 - 100356

ER -

ID: 393780619