PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia

被引:98
作者
Fatemi, S. Hossein [1 ,2 ,3 ]
King, David P. [4 ]
Reutiman, Teri J. [1 ]
Folsom, Timothy D. [1 ]
Laurence, Jessica A. [1 ]
Lee, Susanne [1 ]
Fan, Yu-Ti [5 ]
Paciga, Sara A. [4 ]
Conti, Marco [6 ]
Menniti, Frank S. [7 ]
机构
[1] Univ Minnesota, Dept Psychiat, Div Neurosci Res, Sch Med, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA
[3] Univ Minnesota, Sch Med, Dept Neurosci, Minneapolis, MN 55455 USA
[4] Pfizer Global Res & Dev, Pharmacogen, Groton, CT 06340 USA
[5] Pfizer Global Res & Dev, Stat, Groton, CT 06340 USA
[6] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, Ctr Reprod Sci, San Francisco, CA 94143 USA
[7] Pfizer Global Res & Dev, CNS Discovery, Groton, CT 06340 USA
关键词
schizophrenia; bipolar disorder; major depression; phosphodiesterase; 4B; polymorphisms;
D O I
10.1016/j.schres.2008.01.029
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
Schizophrenia has a complex genetic underpinning and variations in a number of candidate genes have been identified that confer risk of developing the disorder. We report in the present studies that several single nucleotide polymorphisms (SNPs) and a two-SNP haplotype in PDE4B are associated with an increased incidence of schizophrenia in two large populations of Caucasian and African American patients. The SNPs in PDE4B associated with schizophrenia occur in intronic sequences in the vicinity of a critical splice junction that gives rise to the expression of PDE4B isoforms with distinct regulation and function. We also observed specific decreases in phosphodiesterase 4B (PDE4B) isofon-ns in brain tissue obtained postmortem from patients diagnosed with schizophrenia and bipolar disorder. PDE4B metabolically inactivates the second messenger cAMP to regulate intracellular signaling in neurons throughout the brain. Thus, the present observations suggest that dysregulation of intracellular signaling mediated by PDE4B is a significant factor in the cause and expression, respectively, of schizophrenia and bipolar disorder and that targeting PDE4B-regulated signaling pathways may yield new therapies to treat the totality of these disorders. (C) 2008 Elsevier B.V. All rights reserved.
引用
收藏
页码:36 / 49
页数:14
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