Variability in the effect of 5-HTTLPR on depression in a large European population: the role of age, symptom profile, type and intensity of life stressors.

5-HTTLPRxRLE interaction, with PLINK (left column) and Bayesian (right column) analyses.LR+: likelihood ratio of emergence of the disease; BSI: Brief Symptom Inventory; BSI-DEP: BSI depression score; BSI-ANX: BSI anxiety score; DEP: lifetime depression; RLE: recent negative life events (in the last year). The three categories of RLE are: low = 0–1, medium = 2, high = 3 or more. Numbers in groups: low RLE: ss = 292, sl = 746, ll = 480; medium RLE: ss = 82, sl = 207, ll = 144; high RLE: ss = 51, sl = 146, ll = 134. Standard errors of means are displayed in case of continuous variables (left column). Right column figures display outlines of posterior distributions of Bayesian Odds Ratios of 5-HTTLPR ss versus ll genotype with respect to DEP, BSI-DEP (severe vs. low), and BSI-ANX (severe vs. low). Subsets according to RLE categories (low, medium and high) were analyzed individually. Curve flatness refers to the number of possible models, each with a different odds ratio. An odds ratio greater than one represents a risk for the given phenotype. 1A. Logistic regression analysis showed that having the more s alleles increased the risk of DEP with increasing number of RLE. 1B. Regarding DEP there is a clear difference between subjects with low RLE (with a Bayesian Odds Ratio close to 1) and subjects with medium or high RLE (where the effect of ss genotype is stronger). 1C. As in case of DEP: having the more s alleles also increased BSI-DEP with increasing number of RLE, using linear regression analysis. 1D. As in case of DEP: effect of ss genotype on BSI-DEP is negligible in the low RLE group, but higher in the medium, and especially high in the high RLE group. 1E. In contrast to depression phenotypes: linear regression analysis showed that carrying the more s alleles increased BSI-ANX without interaction with RLE. 1F. In contrast to depression phenotypes, ss genotype represents a risk for BSI-ANX irrespective of RLE group.

Effect of age on posterior distribution of Bayesian Odds Ratios of 5-HTTLPR on BSI-ANX.BSI: Brief Symptom Inventory; BSI-ANX: BSI anxiety score. Curves display outlines of posterior distributions of Bayesian Odds Ratios of 5-HTTLPR ss versus ll genotype with respect to BSI-ANX (severe vs. low). An odds ratio greater than 1 represents risk for BSI-ANX. Odds ratios are given in different age groups (all population; equal and below 30; and above 30). All curves are highly peaked that indicates that all the possible models entail highly similar odds ratios, and the Bayesian Odds Ratio values show a moderate 5-HTTLPR ss genotype effect in the total population, strong effect in the younger subjects and negligible effects in the elder subpopulation.

Bayesian posterior probabilities of relevance of 5-HTTLPR for the multivariate phenotype.RLE was grouped into three categories: low = 0–1, medium = 2, high = 3 or more number of recent negative life events (in the past year). CHA (childhood adversity) was divided into two categories (based on the original three): low = 0–3, medium or high = 4 or more scores. Multivariate phenotype (more accurately describes depression related psychiatric state than one phenotype measure alone) encompasses lifetime depression, BSI depression score and BSI anxiety score. Results are displayed according to CHA and age, in groups differentially exposed to RLE. 3A and 3B. Results demonstrate moderate Bayesian probability of relevance of 5-HTTLPR in both age groups and CHA groups in those who had 3 or more RLE. 3C. In the younger age group (≤30) 5-HTTLPR was strongly relevant in those who had medium or high CHA and even moderate number of RLE. 3D. In the older age group (>30) 5-HTTLPR was strongly relevant in those who had 3 or more RLE, irrespective of CHA.