Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders

Abstract

The serotonin transporter is a compelling candidate gene to examine in bipolar and unipolar affective disorder, since drugs that specifically inhibit the serotonin transporter can successfully treat depression. Previous association studies of a VNTR polymorphism in intron 2 and a functional insertion/deletion polymorphism in the promoter of this gene have produced conflicting results. The present study examined allele and genotype frequencies for both of these polymorphisms and resulting haplotypes in 87 English Caucasian bipolar patients, 125 English Caucasian unipolar affective disorder patients, and 174 controls. No significant associations were detected when these unipolar or bipolar cases were compared either separately or as a pooled "affective disorder" group to the controls. A meta-analysis of over 1,400 individuals of European Caucasian origin was then performed, comprising 772 controls, 375 bipolar and 299 unipolar patients for the VNTR polymorphism, and 739 controls, 392 bipolar and 275 unipolar patients for the promoter polymorphism. A significant association of promoter allele 2 was shown with bipolar (estimated odds ratio 1.21; 95% confidence interval 1.00-1.45), unipolar (OR 1.23; 95% CI 1.01-1.42), and combined bipolar + unipolar groups (OR 1.22; 95% CI 1.04-1.42). There was no demonstrable allelic association of the VNTR polymorphism with affective disorder: for the combined bipolar + unipolar group the odds ratios for VNTR alleles 9 and 10, compared with the common allele 12 were 1.05 (95% CI 0.56-1.95) and 0.90 (95% CI 0.77-1.05). These results suggest that the promoter allele 2, which has previously been shown to result in lower levels of serotonin transporter transcription, may be associated with affective disorder risk.

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

“…In total, 17 population-based studies 9,14,33,34,38,46,50,51,56,60,61,66,[68][69][70] and six family-based studies 12,32,42,53,63,74 were about 5-HTTLPR. A total of 16 population-based studies 27,33,35,38,41,47,[49][50][51]54,56,58,60,61,70,75 and four family-based studies 12,52,57,63 were about the intron 2 VNTR. Among the population-based studies, some used matched controls according to the ethnicity 41,47,50,60,66,69 and others explicitly verified the ethnic homogeneity of the sample through the ancestry history.…”

“…Among the population-based studies, some used matched controls according to the ethnicity 41,47,50,60,66,69 and others explicitly verified the ethnic homogeneity of the sample through the ancestry history. 27,33,56 One used an isolated population. 46 One did not mention the ethnicity of the study sample.…”

Early experience and serotonin transporter gene variation interact to influence primate CNS function

“…Thus, the original finding of higher neuroticism and harm avoidance in adult individuals with the short variant of the 5HTTLPR has been replicated and extended to younger individuals 3 and to other anxietyrelated dimensions of personality, [4][5][6] but has also failed replication. [7][8][9][10][11][12][13] Similarly, studies examining possible association between allelic variation in the promoter region of the serotonin transporter gene and risk for unipolar and bipolar depression have produced inconsistent findings (reviewed in Furlong et al 14 ). Among the potential sources for differences among these findings is the possibility that environmental variables may play an important role in the functional expression of the genotype.…”

The 5HT1Dβ Receptor Gene in Bipolar Disorder A Family-based Association Study

“…To date, results from these studies are conflicting, but overall seem to exclude the direct involvement of the 5HT receptor genes 5HT2A (Mahieu et al 1997;Zhang et al 1997;Vincent et al 1999), 5HT2C (Gutierrez et al 1996;Oruc et al 1997), and of the serotonin transporter protein gene (SLC6A4) (Kelsoe et al 1996;Oruc et al 1997;Mendez de Oliveira et al 1998;Esterling et al 1998;Vincent et al 1999;Mundo et al 2000a) in the pathogenesis of BP. However, a recent meta-analysis study of two 5HTT gene polymorphisms in BP and Unipolar Disorder (UP) on more than 1400 individuals of European Caucasian origin showed a mild association of the short allele of the promoter region polymorphism of the SLC6A4 and both BP and UP (Furlong et al 1998).…”