Genome-wide association study of obsessive-compulsive disorder
Open accessAbstract
Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
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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 [16]
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 [16]
DLGAP1 has been implicated in obsessive-compulsive disorders and interacts significantly with Shank proteins, mutations in which have been linked to autism spectrum disorders with impaired social interaction and communication.
“This gene has been implicated in obsessive-compulsive disorders and interacts significantly with Shank proteins, mutations in which have been linked to autism spectrum disorders with impaired social interaction and communication [98–100].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [99]
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References 78 · Cited by 384
- Authors
- Stewart, S. E., Yu, D., Scharf, J. M., Neale, B. M., Fagerness, J. A., Mathews, C. A., Arnold, P. D., Evans, P. D., Gamazon, E. R., Osiecki, L., McGrath, L., Haddad, S., Crane, J., Hezel, D., Illman, C., Mayerfeld, C., Konkashbaev, A., Liu, C., Pluzhnikov, A., Tikhomirov, A., Edlund, C. K., Rauch, S. L., Moessner, R., Falkai, P., Maier, W., Ruhrmann, S., Grabe, H.-J., Lennertz, L., Wagner, M., Bellodi, L., Cavallini, M. C., Richter, M. A., Cook, E. H., Kennedy, J. L., Rosenberg, D., Stein, D. J., Hemmings, S. M. J., Lochner, C., Azzam, A., Chavira, D. A., Fournier, E., Garrido, H., Sheppard, B., Umaña, P., Murphy, D. L., Wendland, J. R., Veenstra-VanderWeele, J., Denys, D., Blom, R., Deforce, D., Van Nieuwerburgh, F., Westenberg, H. G. M., Walitza, S., Egberts, K., Renner, T., Miguel, E. C., Cappi, C., Hounie, A. G., Conceição do Rosário, M., Sampaio, A. S., Vallada, H., Nicolini, H., Lanzagorta, N., Camarena, B., Delorme, R., Leboyer, M., Pato, C. N., Pato, M. T., Voyiaziakis, E., Heutink, P., Cath, D. C., Posthuma, D., Smit, J. H., Samuels, J., Bienvenu, O. J., Cullen, B., Fyer, A. J., Grados, M. A., Greenberg, B. D., McCracken, J. T., Riddle, M. A., Wang, Y., Coric, V, Leckman, J. F., Bloch, M., Pittenger, C., Eapen, V, Black, D. W., Ophoff, R. A., Strengman, E., Cusi, D., Turiel, M., Frau, F., Macciardi, F., Gibbs, J. R., Cookson, M. R., Singleton, A., North American Brain Expression Consortium, Arepalli, S., Cookson, M. R., Dillman, A., Ferrucci, L., Gibbs, J. R., Hernandez, D. G., Johnson, R., Longo, D. L., Nalls, M. A., O'Brien, R., Singleton, A., Traynor, B., Troncoso, J., van der Brug, M., Zielke, H. R., Zonderman, A., Hardy, J., Database, U. B. E., Hardy, J. A., Ryten, M., Smith, C., Trabzuni, D., Walker, R., Weale, M., Crenshaw, A. T., Parkin, M. A., Mirel, D. B., Conti, D. V., Purcell, S., Nestadt, G., Hanna, G. L., Jenike, M. A., Knowles, J. A., Cox, N., & Pauls, D. L.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- University of California, San Francisco (US)
- University of Toronto (CA)
- University of Chicago (US)
- University of Southern California (US)
- McLean Hospital (US)
- University of Bonn (DE)
- University of Göttingen (DE)
- University of Cologne (DE)
- Universitätsmedizin Greifswald (DE)
- Vita-Salute San Raffaele University (IT)
- Sunnybrook Health Science Centre (CA)
- University of Illinois Chicago (US)
- Centre for Addiction and Mental Health (CA)
- Wayne State University (US)
- University of Cape Town (ZA)
- Stellenbosch University (ZA)
- University of California San Diego (US)
- Hospital Nacional de Niños (CR)
- National Institutes of Health (US)
- F. Hoffmann-La Roche AG (CH)
- Vanderbilt University (US)
- Netherlands Institute for Neuroscience (NL)
- Ghent University (BE)
- University of Zurich (CH)
- University of Würzburg (DE)
- Universidade de São Paulo (BR)
- Universidade Federal da Bahia (BR)
- Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz (MX)
- Inserm (FR)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Utrecht University (NL)
- Johns Hopkins University (US)
- New York State Psychiatric Institute (US)
- Butler Hospital (US)
- University of California, Los Angeles (US)
- Yale University (US)
- UNSW Sydney (AU)
- University of Iowa (US)
- University of Milan (IT)
- University of California, Irvine (US)
- Institut Mondor de Recherche Biomédicale (FR)
- Fondation FondaMental (FR)
- UCL Queen Square Institute of Neurology (GB)
- Columbia University (US)
- King's College London (GB)
- University of Michigan (US)
- Corresponding author
- Stewart, S E
- Pauls, D L
- ORCID
- Stewart, S E
- Yu, D
- Scharf, J M
- Neale, B M
- Mathews, C A
- Arnold, P D
- Evans, P D
- Gamazon, E R
- Osiecki, L
- McGrath, L
- Crane, J
- Hezel, D
- Konkashbaev, A
- Liu, C
- Rauch, S L
- Falkai, P
- Ruhrmann, S
- Wagner, M
- Bellodi, L
- Cavallini, M C
- Richter, M A
- Cook, E H
- Kennedy, J L
- Rosenberg, D
- Stein, D J
- Hemmings, S M J
- Azzam, A
- Chavira, D A
- Sheppard, B
- Wendland, J R
- Veenstra-VanderWeele, J
- Denys, D
- Blom, R
- Deforce, D
- Walitza, S
- Egberts, K
- Renner, T
- Cappi, C
- Hounie, A G
- Sampaio, A S
- Vallada, H
- Nicolini, H
- Lanzagorta, N
- Camarena, B
- Delorme, R
- Leboyer, M
- Pato, C N
- Pato, M T
- Heutink, P
- Cath, D C
- Smit, J H
- Samuels, J
- Bienvenu, O J
- Cullen, B
- Fyer, A J
- Grados, M A
- Greenberg, B D
- McCracken, J T
- Riddle, M A
- Leckman, J F
- Bloch, M
- Pittenger, C
- Eapen, V
- Black, D W
- Ophoff, R A
- Strengman, E
- Cusi, D
- Turiel, M
- Frau, F
- Macciardi, F
- Dillman, A
- Ferrucci, L
- Hernandez, D G
- Longo, D L
- Nalls, M A
- Traynor, B
- Troncoso, J
- Zonderman, A
- Ryten, M
- Trabzuni, D
- Walker, R
- Conti, D V
- Purcell, S
- Nestadt, G
- Hanna, G L
- Jenike, M A
- Knowles, J A
- Cox, N
- Pauls, D L
- Venue
- Molecular Psychiatry
- Published
- 2012-08-14
- Volume
- 18
- Issue
- 7
- Pages
- 788-798
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4218751
- OpenAlex
- W2100825937
- Cited by
- 384
- References
- 78
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 18 · 2023: 25 · 2022: 15 · 2021: 53 · 2020: 23 · 2019: 30 · 2018: 30 · 2017: 31 · 2016: 37 · 2015: 26 · 2014: 45 · 2013: 14 · 2012: 4
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-02-12)
- Open access
- bronze
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- VU Research Portal (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- SUNScholar (Stellenbosch University) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Institutes of Health (6u54rr020278-06)
- Medical Research Council (MR/K01417X/1, MR/J006742/1)
- National Institute on Alcohol Abuse and Alcoholism (U10AA008401)
- National Institute on Aging (Z01AG000932)
- National Institute of Mental Health (K23MH085057, MH085057, MH073250, R13MH073250, MH079489, R01MH079489)
- National Institute on Drug Abuse (R01DA013423)
- National Human Genome Research Institute (U01HG004422, U01HG004446, U01HG004438)
- National Cancer Institute (P01CA089392)
- National Institute of Neurological Disorders and Stroke (NS1664829S1, R01NS016648, U01NS040024, R01NS040024, NS40024-07S1)
- National Center for Research Resources (U54-RR020278)
- 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, single nucleotide polymorphisms, DLGAP1, methylation quantitative trait loci, expression quantitative trait loci, postsynaptic density, X chromosome
- MeSH terms
- SAP90-PSD95 Associated Proteins, Frontal Lobe, Humans, Nerve Tissue Proteins, Obsessive-Compulsive Disorder, Parents, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, White People, Genome-Wide Association Study
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