“Schizophrenia-Associated Somatic Copy-Number Variants from 12,834 Cases Reveal Recurrent NRXN1 and ABCB11 Disruptions”, Eduardo A. Maury, Maxwell A. Sherman, Giulio Genovese, Thomas G. Gilgenast, Tushar Kamath, S. J. Burris, Prashanth Rajarajan, Erin Flaherty, Schahram Akbarian, Andrew Chess, Steven A. McCarroll, Po-Ru Loh, Jennifer E. Phillips-Cremins, Kristen J. Brennand, Evan Z. Macosko, James T. R. Walters, Michael O’Donovan, Patrick Sullivan, Jonathan Sebat, Eunjung A. Lee, Christopher A. Walsh2023 (rare mutations, SCZ, neuroscience)⁠:

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 5 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 5 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.