Gender moderates the association between 5-HTTLPR and decision-making under ambiguity but not under risk

Decisions made under ambiguity may involve a different genetic architecture than those made under risk. Because gender moderates the effect of genetic polymorphisms on serotonin function and because there are gender differences in decision-making, the present study examined potential gender moderation of associations between polymorphisms in important serotonin system candidate genes (serotonin transporter [SLC6A4] and tryptophan hydroxylase-2 [TPH2]) and performance on a decision-making task (Iowa Gambling Task, IGT) in healthy, adults (N = 188; 62% women). Subjects were genotyped for the well-studied SLC6A4 promoter variant 5-HTTLPR and a TPH2 single nucleotide polymorphism in intron-8 (rs1386438). Genotype at rs1386438 was not associated with performance on the IGT. A significant gender by 5-HTTLPR genotype interaction effect was detected when decision-making was under ambiguity (i.e. the first block of 20 choices), but not under risk (blocks 2–5). Performance on the first block of 20 choices was not correlated with performance on subsequent blocks, supporting the interpretation that early performance on the IGT indexes decision-making under ambiguity, while performance on blocks 2–5 indexes decision-making under risk. These findings suggest that decision-making under ambiguity and risk may have different genetic architectures and that individual differences in decision-making under ambiguity are associated with genetic variation in SLC6A4.