Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS
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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 × 10(-)(7)). 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 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.
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OCD genome-wide association studies have generally been underpowered, and definitive genome-wide candidates have yet to be fully elucidated.
“in general OCD genome-wide association studies have been underpowered. Definitive genome-wide candidates therefore have yet to be fully elucidated17.”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [15]
A recent meta-analysis showed only a modest association of 2/9 SNPs with OCD, and SLC1A1 has not emerged as a probable locus from recent GWAS studies.
“although a recent meta-analysis showed only a modest association of 2/9 SNPs with OCD 25, and SLC1A1 has not emerged as a probable locus from recent GWAS studies 15,16”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [15]
DLGAP1 interacts with the glutamate receptor GRIK2, also implicated in obsessive-compulsive disorders.
“DLGAP1 interacts with the glutamate receptor GRIK2, also implicated in obsessive-compulsive disorders [101].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [101]
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Guo, W., Samuels, J. F., Wang, Y., Cao, H., Ritter, M., Nestadt, P. S., Krasnow, J., Greenberg, B. D., Fyer, A. J., McCracken, J. T., et al. (2017) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2017.03.011 · Cited by 59 · see citing works
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Fullana, M. A., Abramovitch, A., Via, E., López-Sola, C., Goldberg, X., Reina, N., Fortea, L., Solanes, A., Buckley, M. J., Ramella-Cravaro, V., et al. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.08.008 · Cited by 44 · see citing works
Ketamine in the Treatment of Obsessive-Compulsive Disorder: A Systematic Review
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- Authors
- Mattheisen, M., Samuels, J. F., Wang, Y., Greenberg, B. D., Fyer, A. J., McCracken, J. T., Geller, D. A., Murphy, D. L., Knowles, J. A., Grados, M. A., Riddle, M. A., Rasmussen, S. A., McLaughlin, N. C., Nurmi, E. L., Askland, K. D., Qin, H.-D., Cullen, B. A., Piacentini, J., Pauls, D. L., Bienvenu, O. J., Stewart, S. E., Liang, K.-Y., Goes, F. S., Maher, B., Pulver, A. E., Shugart, Y. Y., Valle, D., Lange, C., & Nestadt, G.
- Affiliations
- University of Bonn (DE)
- Johns Hopkins University (US)
- Brown University (US)
- New York State Psychiatric Institute (US)
- University of California, Los Angeles (US)
- Harvard University (US)
- National Institute of Mental Health (US)
- University of Southern California (US)
- Corresponding author
- Nestadt, G
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2014-05-13
- Volume
- 20
- Issue
- 3
- Pages
- 337-344
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4231023
- OpenAlex
- W2007417768
- Cited by
- 321
- References
- 60
- Citations by year
- 2026: 11 · 2025: 27 · 2024: 16 · 2023: 22 · 2022: 19 · 2021: 33 · 2020: 26 · 2019: 45 · 2018: 28 · 2017: 37 · 2016: 31 · 2015: 16 · 2014: 9
- FWCI
- 36.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- International OCD Foundation
- Lundbeckfonden (R155-2014-1724)
- National Institutes of Health
- National Institute of Mental Health (MH079494, R01MH071507, MH079488, MH071507, MH079487, MH079489, R01MH079489, R01MH079487, R01MH079488, R01MH079494, K23MH094613)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- obsessive-compulsive disorder, genetic susceptibility, PTPRD, DLGAP1, GRIK2, glutamatergic synapses, GABAergic synapses, synaptic development, gene-environment interaction, early-onset OCD
- MeSH terms
- Adult, Chromosomes, Human, Pair 9, Cooperative Behavior, Family Health, Female, Follow-Up Studies, Genotype, Humans, Male, Obsessive-Compulsive Disorder, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Gene Expression Profiling, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Genome-Wide Association Study, Young Adult
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