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.