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Hu, Xian-Zhang; Lipsky, Robert H.; Zhu, Guanshan; Akhtar, Longina A.; Taubman, Julie; Greenberg, Benjamin D.; Xu, Ke; Arnold, Paul D.; Richter, Margaret A.; Kennedy, James L.; Murphy, Dennis L.; Goldman, David
American journal of human genetics, 05/2006, Volume: 78, Issue: 5Journal Article
A functional serotonin transporter promoter polymorphism, HTTLPR, alters the risk of disease as well as brain morphometry and function. Here, we show that HTTLPR is functionally triallelic. The LG allele, which is the L allele with a common G substitution, creates a functional AP2 transcription-factor binding site. Expression assays in 62 lymphoblastoid cell lines representing the six genotypes and in transfected raphe-derived cells showed codominant allele action and low, nearly equivalent expression for the S and LG alleles, accounting for more variation in HTT expression than previously recognized. The gain-of-function LALA genotype was approximately twice as common in 169 whites with obsessive-compulsive disorder (OCD) than in 253 ethnically matched controls. We performed a replication study in 175 trios consisting of probands with OCD and their parents. The LA allele was twofold overtransmitted to the patients with OCD. The HTTLPR LALA genotype exerts a moderate (1.8-fold) effect on risk of OCD, which crystallizes the evidence that the HTT gene has a role in OCD.
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