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

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.

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Acknowledgements

This project is a multiple sites collaborative project of OCD Collaborative Genetics Association Study (OCGAS), which is a collaboration among investigators at seven sites in the United States (namely Brown University, Columbia University, University of Southern California, Johns Hopkins University, Massachusetts General Hospital, University of California at Los Angeles, and the National Institute of Mental Health) funded by NIMH Grant Numbers: MH071507, MH079489, MH079487, MH079488 and MH079494. Qin and Shugart are both supported by IRP (Project number MH002930-04). The views expressed in this presentation do not necessarily represent the views of the NIMH, NIH, HHS or the United States Government.

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Correspondence to Y Y Shugart.

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Qin, H., Samuels, J., Wang, Y. et al. Whole-genome association analysis of treatment response in obsessive-compulsive disorder. Mol Psychiatry 21, 270–276 (2016). https://doi.org/10.1038/mp.2015.32

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