Genome-wide association study of obsessive-compulsive disorder.
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.
Stewart, SE; Yu, D; Scharf, JM; Neale, BM; Fagerness, JA; Mathews, CA; Arnold, PD; Evans, PD; Gamazon, ER; Davis, LK; Osiecki, L; McGrath, L; Haddad, S; Crane, J; Hezel, D; Illman, C; Mayerfeld, C; Konkashbaev, A; Liu, C; Pluzhnikov, A; Tikhomirov, A; Edlund, CK; Rauch, SL; Moessner, R; Falkai, P; Maier, W; Ruhrmann, S; Grabe, H-J; Lennertz, L; Wagner, M; Bellodi, L; Cavallini, MC; Richter, MA; Cook, EH; Kennedy, JL; Rosenberg, D; Stein, DJ; Hemmings, SMJ; Lochner, C; Azzam, A; Chavira, DA; Fournier, E; Garrido, H; Sheppard, B; Umaña, P; Murphy, DL; Wendland, JR; Veenstra-VanderWeele, J; Denys, D; Blom, R; Deforce, D; Van Nieuwerburgh, F; Westenberg, HGM; Walitza, S; Egberts, K; Renner, T; Miguel, EC; Cappi, C; Hounie, AG; Conceição do Rosário, M; Sampaio, AS; Vallada, H; Nicolini, H; Lanzagorta, N; Camarena, B; Delorme, R; Leboyer, M; Pato, CN; Pato, MT; Voyiaziakis, E; Heutink, P; Cath, DC; Posthuma, D; Smit, JH; Samuels, J; Bienvenu, OJ; Cullen, B; Fyer, AJ; Grados, MA; Greenberg, BD; McCracken, JT; Riddle, MA; Wang, Y; Coric, V; Leckman, JF; Bloch, M; Pittenger, C; Eapen, V; Black, DW; Ophoff, RA; Strengman, E; Cusi, D; Turiel, M; Frau, F; Macciardi, F; Gibbs, JR; Cookson, MR; Singleton, A; North American Brain Expression Consortium, ; Hardy, J; UK Brain Expression Database, ; Crenshaw, AT; Parkin, MA; Mirel, DB; Conti, DV; Purcell, S; Nestadt, G; Hanna, GL; Jenike, MA; Knowles, JA; Cox, N; Pauls, DL
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