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.
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Acknowledgements
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.
AUTHOR CONTRIBUTIONS
Manuscript preparation: SE Stewart, JA Knowles, D Yu, JM Scharf, CA Mathews, PD Arnold, E Gamazon, PD Evans, GL Hanna, NJ Cox and DL Pauls. Study design: SE Stewart, JM Scharf, D Yu, JA Knowles, PD Arnold, CA Mathews, BM Neale, JA Fagerness, EH Cook, S Purcell, NJ Cox, G Nestadt and DL Pauls. Data analysis: D Yu, BM Neale, S Purcell, JM Scharf, PD Evans, ER Gamazon, A Tikhomirov, A Pluzhnikov, A Konkashbaev, LK Davis, D Posthuma, E Eskin, C Sabatti, CK Edlund, DV Conti, JA Knowles, NJ Cox. Project management: SE Stewart, JM Scharf, JA Fagerness, MA Jenike and DL Pauls. Sample management and processing: JA Fagerness, S Haddad, JM Scharf, J Crane, C Mayerfeld and DL Pauls. Genotyping: AT Crenshaw, MA Parkin and DB Mirel. Phenotype management: SE Stewart, L Osiecki, D Hezel, C Illmann, JM Scharf and DL Pauls. Case sample collection (ordered by numbers of submitted samples): University of Bonn, Germany: M Wagner, R Moessner (Site PI), P Falkai, W Maier, S Ruhrmann, H-J Grabe, L Lennertz. Italy: L Bellodi, MC Cavallini. Toronto, Canada/Wayne State collaborative: PD Arnold, MA Richter, EH Cook, Jr, JL Kennedy, D Rosenberg. University of Cape Town, South Africa: DJ Stein (Site PI), SMJ Hemmings, C Lochner. UCSF/ Costa Rica collaborative: CA Mathews (Site PI), A Azzam, DA Chavira, E Fournier, H Garrido, B Sheppard, P Umana. National Institute of Mental Health: DL Murphy, JR Wendland. Michigan: GL Hanna (Site PI), J Veenstra-VanderWeele. AMC, Netherlands: D Denys (Site PI), R Blom, D Deforce, F Van Nieuwerburgh, HGM Westenberg. Wurzburg Germany: S Walitza (Site PI), K Egberts, T Renner. Massachusetts General Hospital, Boston: DL Pauls (Site PI), C Illmann, SE Stewart, JM Scharf, SL Rauch. Brazil: EC Miguel (Site PI), C Cappi, AG Hounie, MC do Rosario, AS Sampaio, H Vallada. Mexico: H Nicolini (Site PI), N Lanzagorta, B Camarena. Paris, France: M Leboyer (Site PI), R Delorme. University of Southern California: MT Pato (Site PI), CN Pato, JA Knowles, E Voyiaziakis. VUMC, Netherlands: DC Cath (Site PI), P Heutink, D Posthuma, JH Smit. OCGS, Johns Hopkins collaborative: G Nestadt (Site PI), J Samuels, OJ Bienvenu, B Cullen, AJ Fyer, MA Grados, BD Greenberg, JT McCracken, MA Riddle, Y Wang. Yale University: JF Leckman (Site PI), M Bloch, C Pittenger, V Coric. United Arab Emirates: V Eapen. Iowa: DW Black. Control Sample Collection: University Medical Center, Utrecht: RA Ophoff, E Strengman. University of Bonn: R Moessner (Site PI), M Wagner, P Falkai, W Maier, S Ruhrmann, H-J Grabe, L Lennertz. Data Collection: Italian Control data: F Macciardi, D Cusi, M Turiel, F Frau. eQTL and mQTL data: C Liu. MR Cookson, JR Gibbs and A Singleton for the North American Brain Expression Consortium; J Hardy for the UK Human Brain Expression Database.
North American Brain Expression Consortium
S Arepalli1, MR Cookson1, A Dillman1, L Ferrucci2, JR Gibbs1,3, DG Hernandez1,3, R Johnson4, DL Longo5, MA Nalls1, R O’Brien6, A Singleton1, B Traynor1, J Troncoso6, M van der Brug1,7, HR Zielke4, A Zonderman8;
UK Human Brain Expression Database
JA Hardy3, M Ryten3, C Smith9, D Trabzuni3, R Walker9, Mike Weale10
1Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; 2Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA; 3Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; 4NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, MD, USA; 5Lymphocyte Cell Biology Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; 6Brain Resource Center, Johns Hopkins University, Baltimore, MD, USA; 7ITGR Biomarker Discovery Group, Genentech, South San Francisco, CA, USA; 8Research Resources Branch, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; 9Department of Pathology, The University of Edinburgh, Edinburgh, UK and 10King’s College London, Department of Medical & Molecular Genetics, UK.
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SE Stewart has received funding from the International OCD Foundation (IOCDF) and is a member of the IOCDF Scientific Advisory Committee. PD Arnold reports funding sources including the CIHR, NIH, Ontario Research Foundation, Ontario Brain Institute, DNA Genotek, and the McLaughlin Centre. AB Singleton served as an unpaid consultant to Teva Pharmaceuticals. HJ Grabe has received funds from the German Research Foundation; Federal Ministry of Education and Research Germany; speakers honoraria from Bristol-Myers Squibb, Eli Lilly, Novartis, Eisai, Boehringer Ingelheim; speaker and travel funds from Janssen-Cilag, Eli Lilly, Novartis, AstraZeneca, Lundbeck and SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. R Moessner has been supported by the German Research Foundation (DFG) (grants Wa 731/6 and 731/4), and by the German Federal Ministry for Education and Research (BMBF grant 01GV0907). M Wagner has been supported by the German Research Foundation (DFG) (grants Wa 731/6 and 731/4), and by the German Federal Ministry for Education and Research (BMBF grant 01GV0907). MA Richter has received honoraria from Lundbeck and she is recipient of grant funding from Eli Lilly Canada, Ontario Mental Health Foundation and the Obsessive-Compulsive Foundation. DJ Stein has received research grants and/or consultancy honoraria from Abbott, Astrazeneca, Eli-Lilly, GlaxoSmithKline, Jazz Pharmaceuticals, Johnson & Johnson, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda and Tikvah. JR Wendland is now a full-time employee of F Hoffmann-La Roche J Veenstra-VanderWeele receives research funding from Seaside Therapeutics, Roche Pharmaceuticals and Novartis. GL Hanna, MT Pato and CN Pato receive NIH funding. K Egberts, T Renner and S Walitza received sample collection funding by DFG WA168/1-1. SL Rauch has received research funding from Cyberonics and Medtronic. JA Knowles is a recipient of grant funding from NIH and from NARSAD; he sits on the Scientific Advisory Committee for Next-Generation Sequencing of Life Technologies and is a technical advisor to SoftGenetics; he is on the Scientific Advisory Committee for 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.
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Stewart, S., Yu, D., Scharf, J. et al. Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry 18, 788–798 (2013). https://doi.org/10.1038/mp.2012.85
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DOI: https://doi.org/10.1038/mp.2012.85
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