The influence of psychiatric screening in healthy populations selection: a new study and meta-analysis of functional 5-HTTLPR and rs25531 polymorphisms and anxiety-related personality traits

Abstract

Background: A genetic liability for anxiety-related personality traits in healthy subjects has been associated with the functional serotonin transporter promoter polymorphism (5-HTTLPR), although the data are somewhat conflicting. Moreover, only one study has investigated the functional significance of the 5-HTTLPR/rs25531 haplotypes in relation to anxiety traits in healthy subjects. We tested whether the 5-HTTLPR polymorphism and the 5-HTTLPR/rs25531 haplotypes are linked to Harm Avoidance (HA) using an association study (STUDY I) and a meta-analytic approach (STUDY II).

Methods: STUDY I: A total of 287 unrelated Italian volunteers were screened for DSM-IV Axis I disorders and genotyped for the 5-HTTLPR and rs25531 (A/G) polymorphisms. Different functional haplotype combinations were also analyzed. STUDY II: A total of 44 studies were chosen for a meta-analysis of the putative association between 5-HTTLPR and anxiety-related personality traits.

Results: STUDY I: In the whole sample of 287 volunteers, we found that the SS genotype and S'S' haplotypes were associated with higher scores on HA. However, because the screening assessed by Mini-International Neuropsychiatric Interview (M.I.N.I.) showed the presence of 55 volunteers affected by depression or anxiety disorders, we analyzed the two groups ("disordered" and "healthy") separately. The data obtained did indeed confirm that in the "healthy" group, the significant effects of the SS genotype and S'S' haplotypes were lost, but they remained in the "disordered" group. STUDY II: The results of the 5-HTTLPR meta-analysis with anxiety-related traits in the whole sample confirmed the association of the SS genotype with higher anxiety-related traits scores in Caucasoids; however, when we analyzed only those studies that used structured psychiatric screening, no association was found.

Conclusions: This study demonstrates the relevance to perform analyses on personality traits only in DSM-IV axis I disorder-free subjects. Furthermore, we did not find an association between functional serotonin transporter gene polymorphisms and anxiety traits in healthy subjects screened through a structured psychiatric interview.

Figure 1

Meta-analysis of 5-HTTLPR LL versus carriers S allele. Meta-analysis of association studies of serotonin transporter gene and anxiety-related personality traits measured by NEO and TCI in Caucasoid population. It was used fixed effects model testing the comparison between LL genotype versus carriers S allele. Bars represent individual study 95% CI, with a central block proportional to study effect size, while summary diamond bar represents the pooled effect size estimate and 95% CI.

Figure 2

Meta-analysis of 5-HTTLPR SS versus carriers L allele. Meta-analysis of association studies of serotonin transporter gene and anxiety-related personality traits measured by NEO and TCI in Caucasoid population. It was used fixed effects model testing the comparison between carriers L allele versus SS genotype. Bars represent individual study 95% CI, with a central block proportional to study effect size, while summary diamond bar represents the pooled effect size estimate and 95% CI.