Pharmacogenetics of obsessive-compulsive disorder: Investigations of intragenic and regulatory region genetic variations

Gwyneth Zai; Clement C Zai; Vanessa F Gonçalves; Karen Wigg; Christine Lochner; Dan J Stein; Carol A Mathews; James L Kennedy; Margaret A Richter

doi:10.1016/j.pnpbp.2025.111315

Pharmacogenetics of obsessive-compulsive disorder: Investigations of intragenic and regulatory region genetic variations

Prog Neuropsychopharmacol Biol Psychiatry. 2025 Apr 2:138:111315. doi: 10.1016/j.pnpbp.2025.111315. Epub 2025 Mar 5.

Authors

Gwyneth Zai¹, Clement C Zai², Vanessa F Gonçalves³, Karen Wigg⁴, Christine Lochner⁵, Dan J Stein⁶, Carol A Mathews⁷, James L Kennedy⁸, Margaret A Richter⁹

Affiliations

¹ Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto M5S 1A8, Canada. Electronic address: gwyneth.zai@camh.ca.
² Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto M5S 1A8, Canada; Laboratory Medicine and Pathobiology, University of Toronto, ON M5S 1A8, Canada; Dalla Lana School of Public Health, University of Toronto, ON, M5T 3M7, Canada; Stanley Center for Psychiatric Research, Broad Institute, 75 Ames Street, Cambridge, MA 02142, USA. Electronic address: clement.zai@camh.ca.
³ Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada. Electronic address: vanessa.goncalves@camh.ca.
⁴ The Frederick W. Thompson Anxiety Disorders Centre, Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada. Electronic address: karen.wigg@sunnybrook.ca.
⁵ SA MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch University, South Africa. Electronic address: cl2@sun.ac.za.
⁶ SA MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, South Africa. Electronic address: dan.stein@uct.ac.za.
⁷ Department of Psychiatry, Center for OCD, Anxiety and Related Disorders, and Genetics Institute, University of Florida, United States. Electronic address: carolmathews@ufl.edu.
⁸ Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto M5S 1A8, Canada. Electronic address: jim.kennedy@camh.ca.
⁹ Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto M5S 1A8, Canada; The Frederick W. Thompson Anxiety Disorders Centre, Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada. Electronic address: peggy.richter@sunnybrook.ca.

PMID: 40054571
DOI: 10.1016/j.pnpbp.2025.111315

Abstract

Few pharmacogenetic studies on the use of genetic variations to predict antidepressant response in obsessive-compulsive disorder (OCD) have been published. This study expanded on the limited literature on single nucleotide polymorphisms (SNPs) across previously identified putative susceptibility genes for OCD, by incorporating known functional regulatory elements for all genes of interest. We investigated 17 SNPs in 12 genes implicated in OCD risk in 206 European ancestry OCD patients with selective serotonin reuptake inhibitor (SSRI) antidepressant response data, examining functional polymorphisms in remote regulatory regions. No association was observed between any regulatory region markers tested and drug response. We observed nominally significant associations between SNPs within the serotonin 1B receptor (5HT1B; SNP rs1778258), SLIT and NTRK-like family member 5 (SLITRK5; SNP rs10450811), and fas apoptotic inhibitory molecule 2 (FAIM2; SNP rs706795), with response to any SSRI, which did not survive multiple comparisons. This study supports a potential role for a number of OCD-associated risk genes in response to antidepressant treatment, warranting further investigation.

Keywords: Antidepressant/drug/treatment response; Obsessive-compulsive disorder (OCD); Pharmacogenetics; Regulatory regions.

MeSH terms

Adult
Female
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Obsessive-Compulsive Disorder* / drug therapy
Obsessive-Compulsive Disorder* / genetics
Pharmacogenetics*
Polymorphism, Single Nucleotide* / genetics
Selective Serotonin Reuptake Inhibitors / therapeutic use
Young Adult

Substances

Selective Serotonin Reuptake Inhibitors