Association of PDE11A global haplotype with major depression and antidepressant drug response

Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the intracellular second messengers cAMP and cGMP to their corresponding monophosphates. PDEs play an important role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. We have previously shown that the individual haplotype GAACC in the PDE11A gene was associated with major depressive disorder (MDD) based on block-by-block analysis. There are two PDE genes, PDE11A and PDE1A, located in chromosome 2q31-q32. In this study, we have further explored whether the whole region 2q31-q32 contribute to MDD or antidepressant response 278 depressed Mexican-American participants and 321 matched healthy controls. Although there is no significant interaction between the two genes, the remission rate of individual carrying the combination genotype at rs1880916 (AG/AA) and rs1549870 (GG) is significantly increased. We analyzed the global haplotype by examining 16 single-nucleotide polymorphisms (SNPs) in PDE11A and six SNPs in PDE1A. None of the haplotypes consisting of six SNPs in the PDE1A have a significant difference between depressed and control groups. Among haplotypes consisting of 16 SNPs across 440 kb in the PDE11A gene, 18 common haplotypes (with frequency higher than 0.8%) have been found in the studied population. Six haplotypes showed significantly different frequencies between the MDD group and the control group. The phylogenetic network result for the 16 SNPs showed that several historic recombination events have happened in the PDE11A gene. The frequency of one haplotype is significantly lower in the remitter group than in the nonremitter group for the depressed participants treated with either desipramine or fluoxetine. Thus, our data suggest that the PDE11A global haplotype is associated with both MDD and antidepressant drug response.