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

Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. ORIGINAL RESEARCH Association of PDE11A global haplotype with major depression and antidepressant drug response Huai-Rong Luo Gui-Sheng Wu Chuanhui Dong Mauricio Arcos-Burgos Luciana Ribeiro Julio Licinio Ma-Li Wong Center on Pharmacogenomics, Department of Psychiatry and Behavioral Science, University of Miami Miller School of Medicine, Miami, FL, USA Abstract: 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. Keywords: PDE11A, major depression, antidepressant, haplotype, linkage disequilibrium, recombination Introduction Correspondence: Ma-Li Wong Professor and Vice-Chair for Translational Research, Director of Center on Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Batchelor Children’s Research Institute, 1580 NW 10th Avenue, Room 633-A, Miami, FL 33136, USA Tel +1 305 243 4727 Fax +1 305 2439708 Email The 3', 5'-cyclic nucleotides cAMP and cGMP function as second messengers in a wide variety of signal transduction pathways. 3', 5'-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP to the corresponding 5’-monophosphates and provide a mechanism to downregulate cAMP- and cGMPsignaling. Human PDEs are composed of 21 genes and are categorized into 11 families based on sequence homology, enzymatic properties, and sensitivity to inhibitors.1–3 PDE11A gene is the most recently identified and cloned member of the PDE protein superfamily.4 Four N-terminal transcript variants (PDE11A1, A2, A3, and A4) encoding different isoforms have been found for this gene.5,6 The PDE11A1, A2, and A3 have a catalytic domain and an N-terminus GAF domain, while the full-length form, PDE11A4, contains two GAF domains and a catalytic domain.4–7 The GAF domain in PDE11A is homologous to other signaling molecule as found in PDE2, PDE5, PDE6, and PDE10.1–3,8 The GAF domain is involved in high affinity allosteric cGMP and other small signaling molecules binding. Because of their unique ligandbinding topologies, the GAF domains of PDEs are likely to offer good new targets Neuropsychiatric Disease and Treatment 2009:5 163–170 © 2009 Luo et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) 163 Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Luo et al for rational drug design.9 PDE11A exhibits properties of dual-substrate PDE and hydrolyzes both cAMP and cGMP into AMP and GMP respectively with similar Km values.4–6 The Km for cAMP and cGMP were similar for all the four PDE11A variants.4–6 Haplotypes provide a record of evolution history more accurately than individual single-nucleotide polymorphisms (SNPs), they can also capture linkage disequilibrium (LD) and recombination hotspots information of a genomic region more completely. Individual haplotype results detected by haplotype blocks may vary considerably from different algorithms since the methods for block definition are still under devising and no single approach is appropriate for all datasets.10 If a recombination hotspot occurs within one gene, using this gene as candidate may not be appropriate. An alternative to individual haplotype association study is to perform multimarker association analysis with multiple adjacent markers,11 that is global haplotype. In unrelated individuals, PHASE program has been widely used to infer the most likely haplotype that an individual has inherited.11 Since we previously demonstrated a significant association between an individual haplotype in the PDE11A gene and major depressive disorder (MDD),12 and two PDE genes (PDE11A and PDE1A) are located in chromosome 2q31–q32, we now evaluate if the whole region 2q31–q32 is associated with MDD by analyzing the gene–gene interaction. Combinations of the individual haplotypes in multiple loci might determine the complexity of an individual’s susceptibility for MDD and outcome of antidepressant treatment. Therefore, we aimed to do the haplotype phasing before block partition using PHASE software by examining 16 SNPs across the PDE11A and six SNPs on the PDE1A gene in this study. Materials and methods Participants This study was approved by the IRBs of the University of California Los Angeles and the University of Miami, and it has been registered in ClinicalTrials.gov (NCT00265292). Genomic DNA samples from 599 Mexican-Americans were used in this study: 278 depressed participants enrolled in a pharmacogenetic study of antidepressant treatment response to desipramine or fluoxetine, and 321 age- and sex-matched control participants recruited from the same Mexican-American community in Los Angeles.12,13 Controls were in general good health but were not screened for medical or psychiatric illness. Inclusion criteria included DSM-IV diagnosis of a current unipolar major depressive episode, with a 21-item Hamilton Depres (...truncated)