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) isoforms 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.
Bibliographical noteFunding Information:
Funding for this study was provided by the Stanley Medical Research Institute (SMRI), Grant #06R-1406 (SHF). SMRI had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Grant support by the Stanley Medical Research Institute (Grant #06R-1406) to SHF is gratefully acknowledged. Postmortem brain tissue was donated by The Stanley Medical Research Institute's brain collection courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken.
Copyright 2008 Elsevier B.V., All rights reserved.
- Bipolar disorder
- Major depression
- Phosphodiesterase 4B