Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response.
Cyclic nucleotide phosphodiesterases (PDEs) constitute a family of enzymes that degrade cAMP and cGMP. Intracellular cyclic nucleotide levels increase in response to extracellular stimulation by hormones, neurotransmitters, or growth factors and are down-regulated through hydrolysis catalyzed by PDEs, which are therefore candidate therapeutic targets. cAMP is a second messenger implicated in learning, memory, and mood, and cGMP modulates nervous system processes that are controlled by the nitric oxide (NO)/cGMP pathway. To investigate an association between genes encoding PDEs and susceptibility to major depressive disorder (MDD), we genotyped SNPs in 21 genes of this superfamily in 284 depressed Mexican Americans who participated in a prospective, double-blind, pharmacogenetic study of antidepressant response, and 331 matched controls. Polymorphisms in PDE9A and PDE11A were found to be associated with the diagnosis of MDD. Our data are also suggestive of the association between SNPs in other PDE genes and MDD. Remission on antidepressants was significantly associated with polymorphisms in PDE1A and PDE11A. Thus, we found significant associations with both the diagnosis of MDD and remission in response to antidepressants with SNPs in the PDE11A gene. We show here that PDE11A haplotype GAACC is significantly associated with MDD. We conclude that PDE11A has a role in the pathophysiology of MDD. This study identifies a potential CNS role for the PDE11 family. The hypothesis that drugs affecting PDE function, particularly cGMP-related PDEs, represent a treatment strategy for major depression should therefore be tested.
Wong
Ma-Li
ML
Center on Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. mali@miami.edu
Whelan
Fiona
F
Deloukas
Panagiotis
P
Whittaker
Pamela
P
Delgado
Marcos
M
Cantor
Rita M
RM
McCann
Samuel M
SM
Licinio
Julio
J
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000627:therapeutic use*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D003891:Desipramine / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D017058:Mexican Americans; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D016037:Single-Blind Method
D000928:Antidepressive Agents; D005473:Fluoxetine; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517265:PDE1A protein, human; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human; D003891:Desipramine