Genetic Association of Phosphodiesterases With Human Cognitive Performance.

Mark E. Gurney

doi:10.3389/fnmol.2019.00022

Mark E. Gurney

Open Access

https://doi.org/10.3389/fnmol.2019.00022

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Abstract

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.

Highlights

Multiple recent, large-scale, genome-wide association studies (GWAS) provide an unbiased view of the genetic fine structure of cognitive function in healthy individuals (Lam et al, 2017; Davies et al, 2018; Lee et al, 2018; Savage et al, 2018)
In the largest GWAS study, Genetic Association of Phosphodiesterases With Human Cognition which was conducted by the Social Science Genetic Association Consortium (SSGAC) and 23andMe, educational attainment was supplemented by analyses of self-reported math ability, highest math class, and by a composite score for cognitive performance that allowed the pooling of data collected from subjects across multiple studies that utilized different cognitive assessment tools (Lee et al, 2018)
The analysis identified independent significant single nucleotide polymorphisms (SNPs) and grouped these under a lead SNP to identify regions in approximate linkage equilibrium with each other

Summary

Introduction

Large-scale, genome-wide association studies (GWAS) provide an unbiased view of the genetic fine structure of cognitive function in healthy individuals (Lam et al, 2017; Davies et al, 2018; Lee et al, 2018; Savage et al, 2018). The large GWAS dataset from the SSGCA and 23andMe study provides a means to test the contribution of genetic variation in PDE gene family members to cognitive performance (Figure 1). SNP in PDE1A, PDE1C, PDE2A, PDE4B and PDE4D reached genome-wide significance (P < 5 × 10−8) in the primary GWAS which used educational attainment as a phenotype (Table 1).

Results

Conclusion