Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2


  1. American Psychiatric Association (ed). Diagnostic and statistical manual of mental disorders (DSM-IV). Psychiatric Press: Washington, 1994.

  2. Nestadt G, Grados M, Samuels JF . Genetics of obsessive-compulsive disorder. Psychiatr Clin North Am 2010; 33: 141–158.

    Article  Google Scholar 

  3. Shugart YY, Samuels J, Willour VL, Grados MA, Greenberg BD, Knowles JA et al. Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Mol Psychiatry 2006; 11: 763–770.

    Article  CAS  Google Scholar 

  4. Shugart YY, Wang Y, Samuels JF, Grados MA, Greenberg BD, Knowles JA et al. A family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder in 378 families. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 886–892.

    Article  CAS  Google Scholar 

  5. Voyiaziakis E, Evgrafov O, Li D, Yoon HJ, Tabares P, Samuels J et al. Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study. Mol Psychiatry 2012; 16: 108–120.

    Article  Google Scholar 

  6. Murphy DL, Lesch KP . Targeting the murine serotonin transporter: insights into human neurobiology. Nat Rev Neurosci 2008; 9: 85–96.

    Article  CAS  Google Scholar 

  7. Arnold PD, Rosenberg DR, Mundo E, Tharmalingam S, Kennedy JL, Richter MA et al. Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study. Psychopharmacology (Berl) 2004; 174: 530–538.

    Article  CAS  Google Scholar 

  8. Stewart SE FJ, Moorjani J, Jenike E, Beattie K, Illmann C, Delorme R et al Family-Based Association between Obsessive-Compulsive Disorder and Glutamate Receptor Candidate Genes. World Congress of Psychiatric Genetics: New York, 2007.

    Google Scholar 

  9. Alonso P, Gratacos M, Segalas C, Escaramis G, Real E, Bayes M et al. Association between the NMDA glutamate receptor GRIN2B gene and obsessive-compulsive disorder. J Psychiatry Neurosci 2012; 37: 273–281.

    Article  Google Scholar 

  10. Taylor S . Molecular genetics of obsessive-compulsive disorder: a comprehensive meta-analysis of genetic association studies. Mol Psychiatry 2013; 18: 799–805.

    Article  CAS  Google Scholar 

  11. Stewart SE, Yu D, Scharf JM, Neale BM, Fagerness JA, Mathews CA et al. Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry 2013; 18: 788–798.

    Article  CAS  Google Scholar 

  12. Mattheisen M, Samuels JF, Wang Y, Greenberg BD, Fyer AJ, McCracken JT et al. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS. Mol Psychiatry 2014; 20: 337–344.

    Article  Google Scholar 

  13. Ferguson JM . SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry 2001; 3: 22–27.

    Article  Google Scholar 

  14. Di Bella D, Erzegovesi S, Cavallini MC, Bellodi L . Obsessive-compulsive disorder, 5-HTTLPR polymorphism and treatment response. Pharmacogenomics J 2002; 2: 176–181.

    Article  CAS  Google Scholar 

  15. Brandl EJ, Tiwari AK, Zhou X, Deluce J, Kennedy JL, Muller DJ et al. Influence of CYP2D6 and CYP2C19 gene variants on antidepressant response in obsessive-compulsive disorder. Pharmacogenomics J 2014; 14: 176–181.

    Article  CAS  Google Scholar 

  16. Brandl EJ, Muller DJ, Richter MA . Pharmacogenetics of obsessive-compulsive disorders. Pharmacogenomics 2012; 13: 71–81.

    Article  CAS  Google Scholar 

  17. Sangkuhl K, Klein TE, Altman RB . Selective serotonin reuptake inhibitors pathway. Pharmacogenet Genomics 2009; 19: 907–909.

    Article  CAS  Google Scholar 

  18. Tansey KE, Guipponi M, Perroud N, Bondolfi G, Domenici E, Evans D et al. Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis. PLoS Med 2012; 9: e1001326.

    Article  Google Scholar 

  19. Samuels JF, Riddle MA, Greenberg BD, Fyer AJ, McCracken JT, Rauch SL et al. The OCD collaborative genetics study: methods and sample description. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 201–207.

    Article  Google Scholar 

  20. Nestadt G, Wang Y, Grados MA, Riddle MA, Greenberg BD, Knowles JA et al. Homeobox genes in obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2011; 159B: 53–60.

    Article  Google Scholar 

  21. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 1989; 46: 1006–1011.

    Article  CAS  Google Scholar 

  22. Thornton T, McPeek MS . Case-control association testing with related individuals: a more powerful quasi-likelihood score test. Am J Hum Genet 2007; 81: 321–337.

    Article  CAS  Google Scholar 

  23. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  Google Scholar 

  24. Chelala C, Khan A, Lemoine NR . SNPnexus: a web database for functional annotation of newly discovered and public domain single nucleotide polymorphisms. Bioinformatics 2009; 25: 655–661.

    Article  CAS  Google Scholar 

  25. Hindorff LA MJ, Morales J, Junkins HA, Hall PN, Klemm AK, Manolio TA. et al. A Catalog of Published Genome-Wide Association Studies. URL Accessed on 23 Jan 2013.

  26. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010; 26: 2336–2337.

    Article  CAS  Google Scholar 

  27. Purcell S, Cherny SS, Sham PC . Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003; 19: 149–150.

    Article  CAS  Google Scholar 

  28. Dennis G Jr ., Sherman BT, Hosack DA, Yang J, Gao W, Lane HC et al. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 2003; 4: P3.

    Article  Google Scholar 

  29. Segre AV, Groop L, Mootha VK, Daly MJ, Altshuler D . Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet 2010; 6: e1001058.

    Article  Google Scholar 

  30. Etheridge LA, Crawford TQ, Zhang S, Roelink H . Evidence for a role of vertebrate Disp1 in long-range Shh signaling. Development 2010; 137: 133–140.

    Article  CAS  Google Scholar 

  31. Kim SY, Chung HS, Sun W, Kim H . Spatiotemporal expression pattern of non-clustered protocadherin family members in the developing rat brain. Neuroscience 2007; 147: 996–1021.

    Article  CAS  Google Scholar 

  32. Allen NJ, Bennett ML, Foo LC, Wang GX, Chakraborty C, Smith SJ et al. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 2012; 486: 410–414.

    Article  CAS  Google Scholar 

  33. Jun KR, Hur YJ, Lee JN, Kim HR, Shin JH, Oh SH et al. Clinical characterization of DISP1 haploinsufficiency: A case report. Eur J Med Genet 2013; 56: 309–313.

    Article  Google Scholar 

  34. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 2008; 321: 218–223.

    Article  CAS  Google Scholar 

  35. Redies C, Hertel N, Hubner CA . Cadherins and neuropsychiatric disorders. Brain Res 2012; 1470: 130–144.

    Article  CAS  Google Scholar 

  36. Arnold PD, Macmaster FP, Hanna GL, Richter MA, Sicard T, Burroughs E et al. Glutamate system genes associated with ventral prefrontal and thalamic volume in pediatric obsessive-compulsive disorder. Brain Imaging Behav 2009; 3: 64–76.

    Article  Google Scholar 

  37. Cai J, Zhang W, Yi Z, Lu W, Wu Z, Chen J et al. Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive-compulsive symptoms. Psychopharmacology (Berl) 2013; 230: 49–55.

    Article  CAS  Google Scholar 

  38. Davis KL, Charney D, Coyle JT, Nemeroff C (eds) Neuropsychopharmacology: The Fifth Generation of Progress. Lippincott Williams & Wilkins: Philadelphia, 2002.

  39. Korf BR, Rehm HL . New approaches to molecular diagnosis. JAMA 2013; 309: 1511–1521.

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Y Y Shugart.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links