A Novel Study and Meta‐Analysis of the Genetic Variation of the Serotonin Transporter Promoter in the Italian Population Do Not Support a Large Effect on Alzheimer′s Disease Risk

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder whose clinical onset is mainly characterized by memory loss. During AD progression, behavioral and psychological symptoms of dementia (BPSD) frequently occur. In this paper we evaluated the association between AD and the short/long (S/L) functional polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). The S-allele shows a 2-fold reduced transcriptional rate, causing an imbalance in 5-HT intracellular availability that might in turn trigger behavioral and cognitive alterations. We also genotyped the SLC6A4 promoter functional variant rs25531 (A → G). By comparing the genotypic and allelic frequencies in an Italian population of 235 AD and 207 controls, we found an association between 5-HTTLPR and AD (odds ratio for the L-allele versus the S-allele: 0.74, associated P value = .03), while no difference was found for the rs25531. A meta-analysis of studies in Italy assessing 5-HTTLPR and AD risk gave an estimation of odds ratio for the L-allele versus the S-allele of 0.85 (associated P value = .08). Overall, our findings are not supportive of a large genetic effect of the explored polymorphisms on AD risk.

Investigation of association of serotonin transporter and monoamine oxidase‐A genes with Alzheimer's disease and depression in the VITA study cohort: A 90‐month longitudinal study

“…Consistent with this, we demonstrated that homozygous carriers of the 5HTTLPR S-allele scored 1.15 points higher for the HAMD. However, we did not find any significant association between 5HTTLPR and LOAD, which fits the recent meta-analysis reported by Polito et al [2012], findings by AlzGene, and other reports, which did not show any significant association between 5HTTLPR and AD [Bertram et al, 2007;Feher et al, 2013]. In contrast, several studies reported Associations between diseases and known risk factors were examined with logistic regression.…”

“…In the present study, we examined two of the most frequently evaluated polymorphisms in psychiatric genetics-5HTTLPR and MAOA-uVNTR [Nishimura et al, 2005;Lopez-Leon et al, 2008;Clarke et al, 2010;Fan et al, 2012;Haenisch et al, 2012;Polito et al, 2012]-for pleiotropic effects on LOAD, DE and its EODE, and LODE forms in an age-matched VITA longitudinal study cohort. Our main finding, confirming many previous reports, is for the 5HTTLPR S-allele being the risk allele for DE [Clarke et al, 2010;Haenisch et al, 2012].…”

The association of 5HT2A and 5HTTLPR polymorphisms with Alzheimer’s disease susceptibility: a meta-analysis with 6945 subjects

“…As for 5HTTLPR (L/S), there were 12 studies referring to Caucasians [ 1 , 22 – 23 , 31 – 33 , 40 , 42 – 46 ] and 4 studies referring to Asians [ 34 – 36 , 41 ]. In addition, 5 studies reported APOE ε4 (with/without) subtypes of AD [ 33 , 35 – 36 , 42 , 44 ]. The genetic distributions of the control group in individual study were consistent with the Hardy-Weinberg equilibrium (HWE).…”

“…To date, a total of 16 studies have detected genetic association between 5-HTTLPR (L/S) and the risk of AD. And, 5 studies reported positive results [ 1 , 31 – 33 , 45 ]. We noticed that Polito et al [ 33 ] has conducted a case-control and meta-analysis study with 13 individual studies and showed no significant association between the 5HTTLPR S allele and the risk of AD.…”

“…The genetic correlation of 5-HTTLPR (L/S) and AD was firstly identified by Li et al in British population [ 31 ]. However, this positive result can only be replicated in several Caucasian populations [ 32 – 33 ], but not in Asian populations [ 34 – 36 ]. These discrepancies may be due to insufficient calculated power, different ethnicities, and limited sample sizes in individual studies.…”