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Am J Hum Genet. 2006 May;78(5):815-826. doi: 10.1086/503850. Epub 2006 Mar 28.

Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder.

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Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD.
Butler Hospital, Brown University School of Medicine, Providence; Department of Psychiatry, Brown University School of Medicine, Providence.
Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto.
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD.
Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD. Electronic address:


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 L(G) 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 L(G) alleles, accounting for more variation in HTT expression than previously recognized. The gain-of-function L(A)L(A) 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 L(A) allele was twofold overtransmitted to the patients with OCD. The HTTLPR L(A)L(A) 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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