The influence of the serotonin transporter gene 5-HTTLPR polymorphism on suicidal behaviors: a meta-analysis

Suicidal Behavior (SB) is the second leading cause of death among youths worldwide and the tenth among all age groups. Inherited genetic differences have a role in suicidality with heritability ranging from 30 to 55%. The SLC6A4 5-HTTLPR gene variant has been largely investigated for association with SB, with controversial results. In this work, we sought to determine whether the results of previous meta-analyses were confirmed or modified subsequent to the inclusion of more recent literature data. An electronic literature search was performed to identify relevant studies published until July 2018. Data were analysed through RevMan v5.3. Subgroup and sensitivity meta-analyses were performed considering different SB sub-phenotypes, ethnicity, gender and psychiatric diagnostic categories. Our literature search yielded 1186 articles; among these, we identified 45 pertinent case-control studies (15,341 subjects). No association was found between low-expressing alleles or genotypes (S + L_G alleles or S' carrier genotypes) and SB in the primary analyses. However, low-expressing alleles (S + L_G) were associated with an increased risk of Violent Suicide Attempt (OR = 1.44, C.I. 1.17-1.78, p = .0007). An effect of the same alleles on SB was found in a subpopulation of substance abusers, but this result was not confirmed after the exclusion of healthy subjects from the control group. The other sensitivity meta-analyses did not show any significant effect. Our findings contribute to clarify the conflicting previous evidence by suggesting an association between the 5-HTTLPR and Violent SB. Nonetheless, many other modulators, including environmental factors and epigenetic mechanisms may act to further increase the level of complexity.