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 x 10(-6) and P = 3.44 x 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 x 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 x 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.
Genome-wide association study of obsessive-compulsive disorder / S.E. Stewart, D. Yu, J.M. Scharf, B.M. Neale, J.A. Fagerness, C.A. Mathews, P.D. Arnold, P.D. Evans, E.R. Gamazon, L.K. Davis, L. Osiecki, L. McGrath, S. Haddad, J. Crane, D. Hezel, C. Illman, C. Mayerfeld, A. Konkashbaev, C. Liu, A. Pluzhnikov, A. Tikhomirov, C.K. Edlund, S.L. Rauch, R. Moessner, P. Falkai, W. Maier, S. Ruhrmann, H.J. Grabe, L. Lennertz, M. Wagner, L. Bellodi, M.C. Cavallini, M.A. Richter, E.H. Cook Jr, J. L. Kennedy, D. Rosenberg, D. J. Stein , S. M. Hemmings, C. Lochner, A. Azzam, D. A. Chavira, E. Fournier, H. Garrido, B. Sheppard, P. Umaña, D. L. Murphy, J. R. Wendland, J. Veenstra-VanderWeele, D. Denys, R. Blom, D. Deforce, F. Van Nieuwerburgh, H.G. Westenberg, S. Walitza, K. Egberts, T. Renner, E.C. Miguel, C. Cappi, A.G. Hounie, M. Conceição do Rosário, A.S. Sampaio, H. Vallada, H. Nicolini, N. Lanzagorta, B. Camarena, R. Delorme, M. Leboyer, C.N. Pato, M.T. Pato, E. Voyiaziakis, P. Heutink, D.C. Cath, D. Posthuma, J.H. Smit, J. Samuels, O.J. Bienvenu, B. Cullen, A.J. Fyer, M.A. Grados, B.D. Greenberg, J.T. McCracken, M.A. Riddle, Y. Wang, V. Coric, J.F. Leckman, M. Bloch, C. Pittenger, V. Eapen , D.W. Black, R.A. Ophoff, E. Strengman, D. Cusi, M. Turiel, F. Frau, F. Macciardi, J.R. Gibbs, M.R. Cookson, A. Singleton, J. Hardy, A.T. Crenshaw, M.A. Parkin, D.B Mirel, D.V. Conti, S. Purcell, G. Nestadt, G.L. Hanna, M.A. Jenike, J.A. Knowles, N. Cox, D.L. Pauls, North Amer Brain Expression Conso, UK Brain Expression Database. - In: MOLECULAR PSYCHIATRY. - ISSN 1359-4184. - 18:7(2013 Jul), pp. 788-798. [10.1038/mp.2012.85]
Genome-wide association study of obsessive-compulsive disorder
D. Cusi;M. Turiel;F. Macciardi;
2013
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 x 10(-6) and P = 3.44 x 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 x 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 x 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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