Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q.
Obsessive-compulsive disorder (OCD) is the tenth most disabling medical condition worldwide. Twin and family studies implicate a genetic etiology for this disorder, although specific genes have yet to be identified. Here, we present the first large-scale model-free linkage analysis of both extended and nuclear families using both 'broad' (definite and probable diagnoses) and 'narrow' (definite only) definitions of OCD. We conducted a genome-scan analysis of 219 families collected as part of the OCD Collaborative Genetics Study. Suggestive linkage signals were revealed by multipoint analysis on chromosomes 3q27-28 (P=0.0003), 6q (P=0.003), 7p (P=0.001), 1q (P=0.003), and 15q (P=0.006). Using the 'broad' OCD definition, we observed the strongest evidence for linkage on chromosome 3q27-28. The maximum overall Kong and Cox LODall score (2.67) occurred at D3S1262 and D3S2398, and simulation based P-values for these two signals were 0.0003 and 0.0004, respectively, although for both signals, the simulation-based genome-wide significance levels were 0.055. Covariate-linkage analyses implicated a possible role of gene(s) on chromosome 1 in increasing the risk for an earlier onset form of OCD. We are currently pursuing fine mapping in the five regions giving suggestive signals, with a particular focus on 3q27-28. Given probable etiologic heterogeneity in OCD, mapping gene(s) involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods.
Shugart
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Department of Epidemiology, Johns Hopkins University, Baltimore, MD 21287, USA. yyao@jhsph.edu
Samuels
J
J
Willour
V L
VL
Grados
M A
MA
Greenberg
B D
BD
Knowles
J A
JA
McCracken
J T
JT
Rauch
S L
SL
Murphy
D L
DL
Wang
Y
Y
Pinto
A
A
Fyer
A J
AJ
Piacentini
J
J
Pauls
D L
DL
Cullen
B
B
Page
J
J
Rasmussen
S A
SA
Bienvenu
O J
OJ
Hoehn-Saric
R
R
Valle
D
D
Liang
K-Y
KY
Riddle
M A
MA
Nestadt
G
G
D002877:Chromosomes, Human; D002878:Chromosomes, Human, Pair 1; D002884:Chromosomes, Human, Pair 15; D002893:Chromosomes, Human, Pair 3; D002896:Chromosomes, Human, Pair 6; D002897:Chromosomes, Human, Pair 7; D005192:Family Health; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D008126:Lod Score; D009771:Obsessive-Compulsive Disorder / Q000235:genetics*; D010641:Phenotype