Abstract
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.
Original language | English (US) |
---|---|
Pages (from-to) | 788-798 |
Number of pages | 11 |
Journal | Molecular psychiatry |
Volume | 18 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2013 |
Keywords
- DLGAP
- GWAS
- genetic
- genomic
- neurodevelopmental disorder
- obsessive-compulsive disorder
ASJC Scopus subject areas
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Molecular Biology
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In: Molecular psychiatry, Vol. 18, No. 7, 07.2013, p. 788-798.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genome-wide association study of obsessive-compulsive disorder
AU - Stewart, S. E.
AU - Yu, D.
AU - Scharf, J. M.
AU - Neale, B. M.
AU - Fagerness, J. A.
AU - Mathews, C. A.
AU - Arnold, P. D.
AU - Evans, P. D.
AU - Gamazon, E. R.
AU - Osiecki, L.
AU - McGrath, L.
AU - Haddad, S.
AU - Crane, J.
AU - Hezel, D.
AU - Illman, C.
AU - Mayerfeld, C.
AU - Konkashbaev, A.
AU - Liu, C.
AU - Pluzhnikov, A.
AU - Tikhomirov, A.
AU - Edlund, C. K.
AU - Rauch, S. L.
AU - Moessner, R.
AU - Falkai, P.
AU - Maier, W.
AU - Ruhrmann, S.
AU - Grabe, H. J.
AU - Lennertz, L.
AU - Wagner, M.
AU - Bellodi, L.
AU - Cavallini, M. C.
AU - Richter, M. A.
AU - Cook, E. H.
AU - Kennedy, J. L.
AU - Rosenberg, D.
AU - Stein, D. J.
AU - Hemmings, S. M.J.
AU - Lochner, C.
AU - Azzam, A.
AU - Chavira, D. A.
AU - Fournier, E.
AU - Garrido, H.
AU - Sheppard, B.
AU - Umaña, P.
AU - Murphy, D. L.
AU - Wendland, J. R.
AU - Veenstra-Vanderweele, J.
AU - Denys, D.
AU - Blom, R.
AU - Deforce, D.
AU - Van Nieuwerburgh, F.
AU - Westenberg, H. G.M.
AU - Walitza, S.
AU - Egberts, K.
AU - Renner, T.
AU - Miguel, E. C.
AU - Cappi, C.
AU - Hounie, A. G.
AU - Conceição Do Rosário, M.
AU - Sampaio, A. S.
AU - Vallada, H.
AU - Nicolini, H.
AU - Lanzagorta, N.
AU - Camarena, B.
AU - Delorme, R.
AU - Leboyer, M.
AU - Pato, C. N.
AU - Pato, M. T.
AU - Voyiaziakis, E.
AU - Heutink, P.
AU - Cath, D. C.
AU - Posthuma, D.
AU - Smit, J. H.
AU - Samuels, J.
AU - Bienvenu, O. J.
AU - Cullen, B.
AU - Fyer, A. J.
AU - Grados, M. A.
AU - Greenberg, B. D.
AU - McCracken, J. T.
AU - Riddle, M. A.
AU - Wang, Y.
AU - Coric, V.
AU - Leckman, J. F.
AU - Bloch, M.
AU - Pittenger, C.
AU - Eapen, V.
AU - Black, D. W.
AU - Ophoff, R. A.
AU - Strengman, E.
AU - Cusi, D.
AU - Turiel, M.
AU - Frau, F.
AU - MacCiardi, F.
AU - Gibbs, J. R.
AU - Cookson, M. R.
AU - Singleton, A.
AU - Arepalli, S.
AU - Cookson, M. R.
AU - Dillman, A.
AU - Ferrucci, L.
AU - Gibbs, J. R.
AU - Hernandez, D. G.
AU - Johnson, R.
AU - Longo, D. L.
AU - Nalls, M. A.
AU - O'Brien, R.
AU - Singleton, A.
AU - Traynor, B.
AU - Troncoso, J.
AU - Van Der Brug, M.
AU - Zielke, H. R.
AU - Zonderman, A.
AU - Hardy, J.
AU - Crenshaw, A. T.
AU - Parkin, M. A.
AU - Mirel, D. B.
AU - Conti, D. V.
AU - Purcell, S.
AU - Nestadt, G.
AU - Hanna, G. L.
AU - Jenike, M. A.
AU - Knowles, J. A.
AU - Cox, N.
AU - Pauls, D. L.
AU - Ryten, M.
AU - Smith, C.
AU - Trabzuni, D.
AU - Walker, R.
AU - Weale, Mike
N1 - Funding Information: The authors would like to express their utmost gratitude to the OCD-affected families who participated in this research. In addition, they would like to thank the International OCD Foundation (IOCDF) for their role in establishing the IOCDF Genetics Collaborative, as well as other individuals who played roles in assisting this study, including Rhonda Ellwyn, Katherine Beattie, Colm O’Dushlaine, Doug Ruderfer, Priya Moorjani and V. Guttenthaler. This work was supported primarily by a grant from the Judah Foundation (a private, non-industry related foundation established by a family affected by OCD), NIH grants MH079489 and MH073250 to DLP, American Recovery and Re-investment Act (ARRA) awards NS40024-07S1 and NS16648-29S1 to DLP, by an American Academy of Child and Adolescent Psychiatry (AACAP) Early Investigator Research Grant, an Anxiety Disorders Association of America (ADAA) Junior Investigator Research Grant, the University of British Columbia and a Michael Smith Foundation Clinical Research Scholar Award to SES, and grants from the Tourette Syndrome Association (DLP and JMS), the American Academy of Neurology Foundation (JMS) and NIH grant MH085057 to JMS. The Broad Institute Center for Genotyping and Analysis was supported by grant U54 RR020278 from the National Center for Research Resources. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for related genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract ‘High throughput genotyping for studying the genetic contributions to human disease’ (HHSN268200782096C). The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id= phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. Frontal lobe eQTL data was provided by the North American Brain Expression Consortium and the UK Human Brain Expression Database. Funding support for generation of the eQTL data was provided by the UK Medical Research Council and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services project Z01 AG000932-02. The North American Brain Expression Consortium comprises: Sampath Arepalli, Mark R Cookson, Allissa Dillman, Luigi Ferrucci, J Raphael Gibbs, Dena G Hernandez, Robert Johnson, Dan L Longo, Michael A Nalls, Richard O′Brien, Andrew Singleton, Bryan Traynor, Juan Troncoso, Marcel van der Brug, H Ronald Zielke and Alan Zonderman. The UK Human Brain Expression Database membership comprises: John A Hardy, Mina Ryten, Colin Smith, Daniah Trabzuni, Robert Walker and Mike Weale. None of the funding sources supporting this work had any influence or played any role in: (a) the design or conduct of the study; (b) management, analysis or interpretation of the data; or c) preparation, review or approval of the manuscript. Funding Information: Next-Generation Sequencing of Life Technologies and is a technical advisor to SoftGenetics. JF Leckman has been funded by the NIH, the TSA, Talecris Biotherapeutics, Klingenstein Third Generation Foundation, John Wiley and Sons, McGraw Hill and Oxford University Press. V Coric works for Bristol Myers-Squibb. DW Black has received NIH funding and support from AstraZeneca and Psysadon in addition to royalties from American Psychiatric Publishing and Oxford University Press. The remaining authors declare no conflicts of interest.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
KW - DLGAP
KW - GWAS
KW - genetic
KW - genomic
KW - neurodevelopmental disorder
KW - obsessive-compulsive disorder
UR - http://www.scopus.com/inward/record.url?scp=84879422520&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879422520&partnerID=8YFLogxK
U2 - 10.1038/mp.2012.85
DO - 10.1038/mp.2012.85
M3 - Article
C2 - 22889921
AN - SCOPUS:84879422520
SN - 1359-4184
VL - 18
SP - 788
EP - 798
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 7
ER -