An association between Epac-1 gene variants and anxiety and depression in two independent samples.

Deficiency in signal transduction might play a role in the development of anxiety and depression, as suggested by a study on the involvement of the PKA-independent Epac pathway. We investigated the association between Epac-1 gene variants, also known as RapGEF-3, and measures of anxiety and depression in a Dutch twin-family sample. Replication was sought in a USA sample consisting of unrelated individuals. Genotype and phenotype data were available for 910 Dutch and 684 USA individuals. Longitudinal self-report measures of neuroticism, anxiety and depression and genetic factor scores (GFS-NL), based on these measures, were analyzed in the Dutch sample. In the USA sample, neuroticism and Genetic Factor Scores (GFS-USA), based on neuroticism and diagnoses of anxiety disorders and depression, were analyzed. Three intronic SNPs were genotyped. Analyses were performed in QTDT. Genotype and haplotype frequencies differed significantly between the samples. In the Dutch sample, rs2072115 showed a significant dominant effect for anxiety and depression. Subjects with haplotype G-C-C (ordered rs2072115-rs757281-2074533) had significantly lower anxiety, neuroticism and GFS-NL scores. In the USA sample, a significant additive effect of rs2074533 on GFS-USA was found. Subjects with haplotypes G-C-C and A-C-T had significantly higher and lower GFS-USA scores, respectively. Both samples showed an association between Epac-1 gene variants and anxiety and depression, but for different variants or in opposite directions. The divergent results could be due to differences in linkage disequilibrium between the investigated SNPs and a functional polymorphism in the Dutch and USA sample.