Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response.
Wong, M., Whelan, F., Deloukas, P., et al. Proc. Nat. Acad. Sci., 103(41), 15124-15129 (October 10, 2006).
Phosphodiesterases, which metabolize the cyclic nucleotides c-AMP and c-GMP, have been classified into eleven different families, derived from 21 genes. All of these enzymes are found in the nervous system where cyclic nucleotides play important roles in intracellular regulation and communication. The present study examined single nucleotide polymorphisms of 284 depressed patients and 331 matched controls in an attempt to identify a correlation between specific genetic variants of these enzymes and major depressive disorder and/or its responsiveness to drug therapy.
The results demonstrate a correlation between polymorphisms in phosphodiesterase 11 and both the diagnosis of depression and remission induced by fluoxetine. Five SNPs are associated with the PDE11A gene, which is comparable to several other phosphodiesterases and is far fewer than the number of variants of the phosphodiesterase families 1, 4, and 10. The only other polymorphisms that showed a correlation to depression were phosphodiesterase 9, a c-GMP specific enzyme that was related to disease diagnosis, and phosphodiesterase 1, a mixed c-AMP/c-GMP enzyme (like phosphodiesterase 11) that was correlated to disease remission.
The results suggest that genetic variants of phosphodiesterase 11, the most recently discovered of the cyclic-nucleotide metabolizing enzymes, play a role in at least some cases of depressive illness. This finding may ultimately be exploited to develop new therapies.
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