Schizophrenia-associated somatic copy number variants from 12,834 cases reveal contribution to risk and recurrent, isoform-specific NRXN1 disruptions

While inherited and de novo copy number variants (CNV) have been implicated in the genetic architecture of schizophrenia (SCZ), the contribution of somatic CNVs (sCNVs), present in some but not all cells of the body, remains unknown. Here we explore the role of sCNVs in SCZ by analyzing blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls. sCNVs were more common in cases (0.91%) than in controls (0.51%, p = 2.68e-4). We observed recurrent somatic deletions of exons 1-5 of the NRXN1 gene in 5 SCZ cases. Allele-specific Hi-C maps revealed ectopic, allele-specific loops forming between a potential novel cryptic promoter and non-coding cis regulatory elements upon deletions in the 5’ region of NRXN1 . We also observed recurrent intragenic deletions of ABCB11 , a gene associated with anti-psychotic response, in 5 treatment-resistant SCZ cases. Taken together our results indicate an important role of sCNVs to SCZ risk and treatment-responsiveness. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement 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., 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 the NIH grants (K01 AG051791, DP2 AG072437, R01AG070921) and SUHF foundation. J.S. is supported by NIH grants (MH113715, MH119746, MH109501, MH119746). J.E.P-C and K.J.B. are supported by a Chan Zuckerberg Institute grant (2020-221479). J.E.P-C is supported by NIH grants (DP1OD031253, R01NS-114226, R01MH12026,U01DK127405). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Individual level SNP-array data is part of the Psychiatric Genomic Consortium with the corresponding privacy agreement. Access can be provided by applying through this website (https://www.med.unc.edu/pgc/shared-methods/how-to/) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript. Individual level SNP-array data is part of the Psychiatric Genomic Consortium with the corresponding privacy agreement. Access can be provided by applying through this website (https://www.med.unc.edu/pgc/shared-methods/how-to/)