Serotonin Transporter Promoter Gain-of-Function Genotypes Are Linked to Obsessive-Compulsive Disorder

Abstract

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.

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…It was reported, that in lymphoblastoid cell lines, the S and L G alleles were associated with lower 5-HTT expression compared to the L A allele. 106 However, this finding has not been consistently replicated. 108 It is also unclear whether the rs25531 SNP has any impact on the functionality of the short 5-HTTLPR allele.…”

“…72 However, an additive co-dominant effect was demonstrated in larger samples considering s/l 70 or S, L A /L G alleles. 106 In contrast, human functional neuroimaging studies suggest functionally dominant s allele. 96,98 The human G Â E studies provide an inconsistent picture.…”

“…69,104 An adenosine/guanine (A/G) single-nucleotide polymorphism (SNP) located within the repeats of 5-HTTLPR seems to be relatively common even in Caucasian populations, with a minor (G) allele frequency (MAF) of 10%; it has been described as rs25531 SNP associated with either short or long 5-HTTLPR alleles 105 or as a L A /L G modifier of the long allele. 106 Wendland and colleagues 107 have demonstrated that the disagreement was caused by two alternative demarcations of the 5-HTTLPR insertion sequence and that the G/A rs25531 SNP can be associated with either l or s allele. It was reported, that in lymphoblastoid cell lines, the S and L G alleles were associated with lower 5-HTT expression compared to the L A allele.…”

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

“…39,40 A wider list of polymorphism should be investigated to achieve a better resolution given that other control regions may be present for the 5-HTT expression, not to mention possible enhancers or silencers located in other regions far from the gene locus. In fact, Hamilton et al 28,41 reported a significant association of a functional SNP (rs25531) 42,43 located just upstream of the 5-HTTLPR with antidepressant response to fluoxetine treatment and in linkage disequilibrium (LD) with 5-HTTLPR. In the presence of the g allele of this SNP, the l allele of 5-HTTLPR seems to be associated with nonresponse, while this is the case for the s allele in presence of the a allele of the SNP.…”

Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project

“…These included rs25531, a single-nucleotide polymorphism (SNP) suggested to modulate the effects of the 5-HTTLPR on expression of SLC6A4. 23 We hypothesized that as SLC6A4 moderates the effects of stress and encodes the main target for escitalopram, the occurrence of SLEs and any interactions identified would predict response to this drug and not to nortriptyline.…”