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

By Xian-zhang Hu, Robert Lipsky, Guanshan Zhu, Longina A. Akhtar, J. Taubman, B. Greenberg, Ke Xu, P. Arnold, M. Richter, J. Kennedy and 2 more. American Journal of Human Genetics, 2006

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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.

Subfields: Cellular and Molecular Neuroscience, Clinical Psychology, Cognitive Neuroscience

View Paper: https://www.semanticscholar.org/paper/92b771ad4c31a4f3ddff23d95f8563db2f2894b0

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Citations in the corpus

Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. (2008, background): “, rs25531, VNTR-2), which have the potential to moderate the effects of the 5-HTTLPR on gene expression (47,48) and subsequent biological processes (including amygdala activation) potentially sensitive to alterations in serotonergic neurotransmission.”
Emotion-based Dispositions to Rash Action: Positive and Negative Urgency (2008, neutral): “The s and the Lg alleles tend to be relatively low-expressing (they are present less often), and they are associated with lower brain levels of 5HT (Beitchman et al., 2006; Hu et al., 2006; Hu et al., 2005; Lakatos et al., 2003).”
Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. (2008, critical): “However, to date, although there are intriguing findings concerning, for example, the serotonin transporter gene (SERT) (Hu et al., 2006), candidate gene association studies have not yet provided sufficient consistent evidence to confirm specific gene involvement in OCD.”
Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. (2012, neutral): “…in function of the serotonin transporter in carriers of the S-allele, seen in in vitro as well as in vivo imaging studies (Heils et al., 1996; Hu et al., 2006; Willeit and Praschak-Rieder, 2010), thus seems to lead to altered emotional brain activation pattern that might increase the risk…”
Evidence of Genetic and Environmental Effects On the Development of Low Self-Control (2009, background): “Additionally, the serotonin transporter gene has a polymorphism in the promoter region (5HTTLPR), and alleles of this polymorphism have been shown to affect the function and the level of serotonin (Heils et al., 1996; Hu et al., 2006; Lesch et al., 1996; Reist, Mazzanti, Vu, Tran, & Goldman, 2001).”
Natural born killers: The genetic origins of extreme violence (2009, background): “The 5HTTLPR polymorphism is functional, where the low expressing alleles have been found to suppress transcription of the serotonin transporter protein (Hu et al., 2006; Lesch et al., 1996 ).”
A Genome-Wide Analysis of Liberal and Conservative Political Attitudes (2011, background): “We further elaborate on the identified genetic markers as to their potential influence on political attitudes.”