Abstract

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 107). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 106, experiment-wide significant), as well as OFCC1 (P=6.29 × 105). The suggestive findings in this study await replication in larger samples.

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Acknowledgements

The OCD Collaborative Genetics Association Study (OCGAS) is a collaborative research study and was funded by the following NIMH Grant Numbers: MH071507, MH079489, MH079487, MH079488 and MH079494. Y-YS and H-DQ were also supported by the Intramural Research Program of the NIMH. We thank the families who have participated in the study; David Houseman, PhD, Kathleen Merikangas, PhD, and Alec Wilson, PhD, for consultation; and the clinicians, study managers and clinical interviewers at the respective study sites for their efforts in participant recruitment and clinical assessments: Columbia University: Blair Simpson, MD, PhD, Julianna Stevens, BA Katie Buchholz; Johns Hopkins University: Graham Redgrave, MD, Krista Vermillion, BA, Janice Krasnow, PhD, Jana Drew, PhD, Melissa Meyers, PhD, and Margaret Schlossberg, PhD; Harvard/Massachusetts General Hospital: Elizabeth Mancuso, BA, Alyssa Faro, BA, Ashley Brown, BA, Kesley Ramsay, BA; National Institute of Mental Health (NIMH): Theresa B DeGuzman.

Author information

Affiliations

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

    • M Mattheisen
  2. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

    • M Mattheisen
    •  & C Lange
  3. Department of Genomic Mathematics, University of Bonn, Bonn, Germany

    • M Mattheisen
    •  & C Lange
  4. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • J F Samuels
    • , Y Wang
    • , M A Grados
    • , M A Riddle
    • , B A Cullen
    • , O J Bienvenu
    • , F S Goes
    • , A E Pulver
    •  & G Nestadt
  5. Department of Psychiatry and Human Behavior, Brown Medical School, Providence, RI, USA

    • B D Greenberg
    • , S A Rasmussen
    • , N C McLaughlin
    •  & K D Askland
  6. New York State Psychiatric Institute, College of Physicians and Surgeons at Columbia University, New York, NY, USA

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

    • J T McCracken
    • , E L Nurmi
    •  & J Piacentini
  8. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • D A Geller
    • , D L Pauls
    •  & S E Stewart
  9. Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD, USA

    • D L Murphy
  10. Department of Psychiatry and Behavioral SciencesKeck School of Medicine at the University of Southern California, Los Angeles, CA, USA

    • J A Knowles
  11. Division of Intramural Research Program, National Institute of Mental Health, Unit of Statistical Genomics, Intramural Research Program, Bethesda, MD, USA

    • H-D Qin
    •  & Y Y Shugart
  12. Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada

    • S E Stewart
  13. Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    • K-Y Liang
    •  & B Maher
  14. Institute of Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • D Valle

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Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to M Mattheisen or G Nestadt.

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DOI

https://doi.org/10.1038/mp.2014.43

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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