Original ArticlesIdentification of rare mutations of the vasoactive intestinal peptide receptor 2 gene in schizophreniaChen, Chia-Hsianga,b; Cheng, Min-Chihc; Hu, Tsung-Mingc; Ping, Lieh-Yungc; Kushima, Itarud,e; Aleksic, Brankod Author Information aDepartment of Psychiatry, Chang Gung Memorial Hospital, Taoyuan bDepartment and Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan cDepartment of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan dDepartment of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya eMedical Genomics Center, Nagoya University Hospital, Aichi, Nagoya, Japan Received 23 August 2021 Accepted 25 January 2022 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.psychgenetics.com. Correspondence to Chia-Hsiang Chen, MD, PhD, Department of Psychiatry Chang Gung Memorial Hospital at Linkou, No. 5 Fuxing St, Kueishan District, Taoyuan City 333, Taiwan, Tel: +886 3 3281200 x. 2439; fax: +886 3 2380267; e-mail: [email protected] Psychiatric Genetics 32(3):p 125-130, June 2022. | DOI: 10.1097/YPG.0000000000000313 Buy SDC Metrics Abstract Objective Studies showed that rare copy number variations (CNVs) encompassing the vasoactive intestinal peptide receptor 2 gene (VIPR2) were associated with schizophrenia, indicating VIPR2 is a risk gene for schizophrenia. We hypothesized that besides CNV, rare pathogenic single-nucleotide variant (SNV) or small insertion/deletion (Indel) of VIPR2 might be present in some patients and contribute to the pathogenesis of schizophrenia. Methods We performed genome-wide CNV analysis to screen CNV at the VIPR2 locus and targeted sequencing of all the exons of VIPR2 to search for SNV and indel in a sample of patients with chronic schizophrenia from Taiwan. Results We detected a 230-kb microduplication encompassing the VIPR2 in 1 out of 200 patients. Furthermore, we identified six ultrarare SNVs, including one splicing SNV and five missense SNVs, in 516 patients. In-silico analyses showed these SNVs had a damaging effect on the function of VIPR2. Conclusion Our findings support the idea that besides CNV, rare pathogenic SNVs of VIPR2 might contribute to the pathogenesis of schizophrenia in some patients. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.