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.