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

Abstract

The serotonin transporter (5-HTT) is a candidate gene for bipolar disorder (BPD). It has been investigated for association with the illness in a series of studies, but overall results have been inconsistent and its role in the disorder remains controversial. Systematic reviews using metaanalytical techniques are a useful method for objectively and reproducibly assessing individual studies and generating combined results. We performed two meta-analyses of published studies-both population-based and family-based studies-investigating the association between BPD and the 5-HTT gene-linked polymorphic region (5-HTTLPR) and the intron 2 variable numbers of tandem repeats (VNTR) polymorphisms. The literature was searched using Medline and Embase to identify studies for inclusion. We statistically joined population-based and family-based studies into a single meta-analysis. For both polymorphisms, our review revealed significant pooled odds ratios (ORs): 1.12 (95% CI 1.03-1.21) for the 5-HTTLPR and 1.12 (95% CI 1.02-1.22) for the intron 2 VNTR. Meta-regression showed that neither the study type (population-based vs family-based; P ¼ 0.41 for the 5-HTTLPR and P ¼ 0.91 for the intron 2 VNTR) nor the sample ethnicity (Caucasian vs non-Caucasian; P ¼ 0.35 for the 5-HTTLPR and P ¼ 0.66 for the intron 2 VNTR) significantly contributed to the heterogeneity of the meta-analyses. The observed ORs could be regarded simply as a very small but detectable effect of the 5-HTT, which has an additive effect when combined with other susceptibility loci. Alternative hypotheses on this finding were also discussed: a stronger effect of the haplotypes involving the two polymorphisms or other SNP markers; a more direct effect of these polymorphisms on specific phenotypes of BPD; and the presence of gene-environment interaction as a mediator of the genetic effects of 5-HTT. Keywords: bipolar disorder; serotonin transporter; polymorphisms; genetics; association study; meta-analysis Bipolar disorder (BPD), also known as manic-depressive illness, is a frequent and severe psychiatric disorder with the lifetime prevalence between 1 and 2% in the general population, being equally distributed across sexes. 1 The etiology is unknown although the presence of a complex dysfunction at multiple levels such as neurotransmitter system, prefrontallimbic-subcortical circuit and neuroendocrinological system has been suggested. 2 Family studies have indicated a marked increase in lifetime risk of the illness in first-degree relatives of the proband, varying between five and 10 times that of the general population. 3 Twin studies have shown an increased risk in monozygotic co-twins compared with dizygotic co-twins of a proband with BPD. The risk in monozygotic co-twins has been estimated at 45-75 times that of the general population. 3,4 Adoption studies have also shown that the risk of BPD is greater in biological relatives than in adoptive relatives of the probands. 5 Most of the segregation studies have shown that the inheritance of BPD cannot be explained b...

Suicide ideators and attempters with schizophrenia – The role of 5-HTTLPR, rs25531, and 5-HTT VNTR Intron 2 variants

“…In another study performed among the Croatian population, authors reported that this allele was present in 1% of the healthy controls, and 2% of suicide victims. This allele seems to be rare in other European Caucasian populations (healthy controls) as well -English 3%, French and german 1%, Scottish 1%, Spanish 2% (Cho et al, 2005).…”

Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR

“…39,41,42,58 Clinical association studies have further examined the relationship between SERTLPR alleles and psychiatric disorders and anxiety-related personality traits, [59][60][61][62][63][64][65][66] suicide, 67,68 alcoholism, 69,70 response to antidepressants [71][72][73] and brain function as revealed by MRI scans. [74][75][76][77] Although many studies have reported correlations between SERTLPR alleles and SERT expression levels or clinical phenotype, almost an equal number of studies have not.…”

Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis

“…We integrated population-based and family-based association studies into a single meta-analysis using the method described in detail elsewhere (Cho et al, 2005;Kazeem and Farrall, 2005;Lohmueller et al, 2003). Briefly, counts of alleles in case and control groups in population-based studies were summarized in two-by-two tables.…”