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

Molecular Psychiatry volume 21, pages 270–276 (2016)Cite this article

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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.

Author information

Authors and Affiliations

  1. Division of Intramural Research Programs, Unit on Statistical Genomics, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    H Qin & Y Y Shugart

  2. Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    J F Samuels, Y Wang, M A Grados, M A Riddle, B A Cullen, O J Bienvenu, F S Goes, B Maher & G Nestadt

  3. Department of Epidemiology, Tulane University, School of Public Health and Tropical Medicine, New Orleans, LA, USA

    Y Zhu

  4. Department of Psychiatry and Human Behavior, Brown Medical School, Butler Hospital, Brown University, Providence, RI, USA

    B D Greenberg, S A Rasmussen & D Pauls

  5. Department of Psychiatry, Keck Medical School, University of Southern California, Los Angeles, CA, USA

    J A Knowles

  6. College of Physicians and Surgeons, Columbia University, New York, NY, USA

    A J Fyer

  7. Department of Psychiatry and Biobehavioral Sciences, School of Medicine, University of California, Los Angeles, CA, USA

    J T McCracken & J Piacentini

  8. Laboratory of Clinical Science, NIMH, NIH, Bethesda, MD, USA,

    D L Murphy

  9. Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    D Geller

  10. Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada

    S E Stewart

  11. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    A E Pulver

  12. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    D Valle

  13. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    D Valle

  14. Department of Molecular Biology & Genetics, Johns Hopkins University School of Medicine, Institute of Human Genetics, Baltimore, MD, USA

    D Valle

  15. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

    C Lange & M Mattheisen

  16. Department of Genomic Mathematics, University of Bonn, Bonn, Germany

    C Lange & M Mattheisen

  17. Department of Biomedicine and Center for Integrated Sequencing (iSEQ), Aarhus University, Aarhus, Denmark

    M Mattheisen

  18. Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA

    N C McLaughlin

  19. Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    K-Y Liang

  20. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Jane and Terry Semel Institute of Neuroscience and Human Behavior, Los Angeles, CA, USA

    E L Nurmi

  21. Department of Psychiatry and Human Behavior, Butler Hospital, Warren Alpert School of Medicine of Brown University, Providence, RI, USA

    K D Askland

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  1. H Qin
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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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