PMID- 30800055
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 1662-5099 (Print)
IS  - 1662-5099 (Electronic)
IS  - 1662-5099 (Linking)
VI  - 12
DP  - 2019
TI  - Genetic Association of Phosphodiesterases With Human Cognitive Performance.
PG  - 22
LID - 10.3389/fnmol.2019.00022 [doi]
LID - 22
AB  - Recent, large-scale, genome-wide association studies (GWAS) provide a first view 
      of the genetic fine structure of cognitive performance in healthy individuals. 
      These studies have pooled data from up to 1.1 million subjects based on simple 
      measures of cognitive performance including educational attainment, self-reported 
      math ability, highest math class taken, and pooled, normalized scores from 
      cognitive tests. These studies now allow the genome-wide interrogation of genes 
      and pathways for their potential impact on human cognitive performance. The 
      phosphodiesterase (PDE) enzymes regulate key cyclic nucleotide signaling 
      pathways. Many are expressed in the brain and have been the targets of CNS drug 
      discovery. Genetic variation in PDE1C, PDE4B and PDE4D associates with multiple 
      measures of human cognitive function. The large size of the human PDE4B and PDE4D 
      genes allows genetic fine structure mapping to transcripts encoding dimeric 
      (long) forms of the enzymes. Upstream and downstream effectors of the cAMP 
      pathway modulated by PDE4D [adenylate cyclase 1 (ADCY1), ADCY8, PRKAR1A, CREB1, 
      or CREBBP] did not show genetic association with cognitive performance, however, 
      genetic association was seen with brain derived neurotrophic factor (BDNF), a 
      gene whose expression is modulated by cAMP. Notably absent was genetic 
      association in healthy subjects to targets of CNS drug discovery designed to 
      improve cognition in disease states by the modulation of cholinergic 
      [acetylcholinesterase (ACHE), choline acetyltransferase (CHAT), nicotinic alpha 7 
      acetylcholine receptor (CHRNA7)], serotonergic (HTR6), histaminergic (HRH3), or 
      glutamatergic (GRM5) pathways. These new data provide a rationale for exploring 
      the therapeutic benefit of selective inhibitors of PDE1C, PDE4B and PDE4D in CNS 
      disorders affecting cognition.
FAU - Gurney, Mark E
AU  - Gurney ME
AD  - Tetra Discovery Partners, Grand Rapids, MI, United States.
LA  - eng
GR  - R43 MH091791/MH/NIMH NIH HHS/United States
GR  - R44 MH091791/MH/NIMH NIH HHS/United States
GR  - R43 MH107077/MH/NIMH NIH HHS/United States
GR  - R41 NS090666/NS/NINDS NIH HHS/United States
GR  - R44 MH107077/MH/NIMH NIH HHS/United States
GR  - R44 AG054243/AG/NIA NIH HHS/United States
GR  - U01 NS078034/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Review
DEP - 20190208
PL  - Switzerland
TA  - Front Mol Neurosci
JT  - Frontiers in molecular neuroscience
JID - 101477914
PMC - PMC6376954
OTO - NOTNLM
OT  - BDNF
OT  - PDE1C
OT  - PDE2A
OT  - PDE4B
OT  - PDE4D
OT  - brain derived neurotrophic factor
OT  - cognition
OT  - phosphodiesterase
EDAT- 2019/02/26 06:00
MHDA- 2019/02/26 06:01
PMCR- 2019/01/01
CRDT- 2019/02/26 06:00
PHST- 2018/09/05 00:00 [received]
PHST- 2019/01/21 00:00 [accepted]
PHST- 2019/02/26 06:00 [entrez]
PHST- 2019/02/26 06:00 [pubmed]
PHST- 2019/02/26 06:01 [medline]
PHST- 2019/01/01 00:00 [pmc-release]
AID - 10.3389/fnmol.2019.00022 [doi]
PST - epublish
SO  - Front Mol Neurosci. 2019 Feb 8;12:22. doi: 10.3389/fnmol.2019.00022. eCollection 
      2019.