Genome-wide association study on antipsychotic-induced weight gain in Europeans and African-Americans

Malgorzata Maciukiewicz, Arun K. Tiwari, Clement C. Zai, Ilona Gorbovskaya, Christopher P. Laughlin, Erika L. Nurmi, Jeffrey A. Liebermann, Herbert Y. Meltzer, James L. Kennedy, Daniel J. Müller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Background: Antipsychotic (AP) medications are the first line of treatment for schizophrenia. However, most conferr a risk of antipsychotic-induced weight gain (AIWG). The objective of this investigation was to conduct a genome-wide association study (GWAS) of AIWG, followed by comprehensive, post-GWAS approaches. Methods: We investigated n = 201 schizophrenia or schizoaffective disorder patients of European and African American ancestry who were treated primarily with clozapine or olanzapine. We conducted a genome-wide association analysis for AIWG, defined primarily as a percentage of weight change from baseline. Results: When examining Europeans (n = 147), we noticed an association between rs62097526 (β = 0.39, p = 3.59 × 10−6, CADD = 2.213) variant, located downstream of the CIDEA gene, which is considered a risk factor for AIWG. In the entire sample, we observed a significant association between rs1525085 (β = 0.411, p = 3.15 × 10−9) variant of the DGKB gene and AIWG. The association was nominally significant in Europeans (β = 0.271, p = 0.002) and African Americans (β = 0.579, p = 5.73 × 10−5) with the same risk allele. Our top genes (p < 5 × 10−5) were enriched in the GWAS catalog for the risk of obesity and interacted with the known risk factors for obesity (G6PD) and diabetes (IRS1). In addition, these genes are targeted by miRNAs related to schizophrenia (mir-34a) and obesity (mir-19b). However, our polygenic risk score analyses did not provide support for major genetic overlap between obesity and the risk of AIWG. Conclusions: In summary, we propose that the CIDEA and DGKB genes are risk factors for AIWG in transethnic populations. Additionally, our evidence suggests that the G6PD and IRS1 gene-related pathways might be involved in AIWG.

Original languageEnglish (US)
Pages (from-to)204-212
Number of pages9
JournalSchizophrenia Research
Volume212
DOIs
StatePublished - Oct 2019

Funding

DJM is supported by the Canadian Institutes of Health Research (CIHR Operating Grant MOP 142192 ), the National Institutes of Health ( R01MH085801 ), the Centre for Addiction and Mental Health Foundation (Joanne Murphy Professorship) and received a Brain & Behaviour Research (NARSAD) Independent Investigator Award, the Michael Smith New Investigator Salary Prize for Research in Schizophrenia (CIHR).This investigation received approval from the Centre of Addiction and Mental Health Research Ethics Board. We are indebted to all the patients participating in our research.

Keywords

  • Antipsychotic-induced weight gain (AIWG)
  • Diacylglycerol kinase beta (DGKB)
  • GWAS
  • Schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

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