PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia.
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.
Fatemi
S Hossein
SH
Department of Psychiatry, University of Minnesota Medical School, MMC 392, Minneapolis, MN 55455, USA. fatem002@umn.edu
King
David P
DP
Reutiman
Teri J
TJ
Folsom
Timothy D
TD
Laurence
Jessica A
JA
Lee
Susanne
S
Fan
Yu-Ti
YT
Paciga
Sara A
SA
Conti
Marco
M
Menniti
Frank S
FS
D000704:Analysis of Variance; D001714:Bipolar Disorder / Q000235:genetics; D044383:Black People; D001921:Brain / Q000378:metabolism; D016009:Chi-Square Distribution; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D044465:White People; D001741:Black or African American
D054703:Cyclic Nucleotide Phosphodiesterases, Type 4