Introduction: The short (S) allele of a deletion/insertion polymorphism (5-HTTLPR) within the 5-HT transporter gene SLC6A4A is associated with lower levels of serotonin (5-HT) transporters and decreased 5-HT reuptake compared to the long (L) allele (Lesch et al., 1996). 5-HTTLPR S and LG (a variant within the rs25531 SNP functionally similar to S; Wendland et al., 2006) alleles have been associated with smaller hippocampal volumes among healthy controls. It has been suggested that S allele carriers have superior memory compared to L carriers but are more susceptible to deficits following stress (i.e. acute tryptophan depletion and depression; Roiser et al., 2006; Frodl et al., 2008). The aim of this study is to investigate the contribution of the 5-HTTLPR genotype and its interaction with gender and sub-clinical depressive symptoms on hippocampal volume (HC) and memory in healthy young adults.
Method: Participants were 51 controls (25 female) meeting eligibility requirements (ages 18-25, no history of medical/neurologic illness or injury, no DSM-IV Axis I diagnosis, no heavy drug or alcohol use). Verbal memory variables included CVLT-2 immediate and delayed recall, retention, and recognition; visual memory variables included RCFT recall and recognition and WMS-III Faces memory. The BDI-II evaluated depressive symptoms. T1-weighted, 3-D anatomical brain images were obtained from a 4T Varian MRI scanner at the Center for Imaging Research. Left and right hippocampi were manually traced in AFNI after achieving reliability and analyzed as ratios of intracranial volume. Dr. Judith Strong performed genotyping. A series of multiple regressions examined whether 5-HTTLPR single biomarker genotype (SS, SL vs. LL) or two biomarker genotype (SS, SLA, SLG, LGLG, LALG vs. LALA) predicted memory variables and (HC). A second block examined the interaction with depressive symptoms.
Results: After controlling for verbal ability, gender, BMI, BDI-II, and cotinine levels, two biomarker genotype was interactively associated with gender in predicting larger HC among S or LG females and smaller HC among S or LG males. A three way interaction between single biomarker genotype, gender, and depressive symptoms significantly predicted larger left HC among S females as depressive symptoms increased (opposite direction for men). Single biomarker genotype was interactively associated with gender in predicting poorer visual recall among S females and with increased depression in marginally predicting poorer verbal immediate memory among S allele carriers.
Discussion: In this healthy, young adult population, the 5-HTTLPR genotype interacted with gender and depressive symptoms in predicting these neurocognitive variables; there were no independent predictions associated with genotype alone. Considered a “risk” for female carriers, the S allele was associated with larger HC. The S allele was considered a “risk” allele for females (larger HC, poorer memory) and for those with increased depressive symptoms. Larger, longitudinal studies examining 5-HTTLPR and possible epigenetic mechanisms among clinical and substance-using male and female populations are necessary. Research in this field could aid in early detection of genetic risk factors and inform possible interventions.