Whole-genome association analysis of treatment response in obsessive-compulsive disorder

Mol Psychiatry. 2016 Feb;21(2):270-6. doi: 10.1038/mp.2015.32. Epub 2015 Mar 31.

Abstract

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Obsessive-Compulsive Disorder / genetics*
  • Polymorphism, Single Nucleotide
  • Selective Serotonin Reuptake Inhibitors / metabolism
  • Selective Serotonin Reuptake Inhibitors / therapeutic use
  • Self Report
  • Treatment Outcome

Substances

  • Membrane Proteins
  • Serotonin Uptake Inhibitors