Genetic Association of Phosphodiesterases With Human Cognitive Performance

Gurney, Mark E.

doi:10.3389/fnmol.2019.00022

Cited by 23 publications

(19 citation statements)

References 62 publications

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“…In 2019, a meta-analysis carried out with the inclusion of 1.1 million mentally healthy individuals confirmed the allelic association of the BDNF gene and phosphodiesterases PDE1C, PDE4B, PDE4D with differences in cognitive traits such as educational level and mathematical abilities. The measurement was performed using normalized cognitive test scores (Gurney, 2019).…”

Section: Genetic Studies Of Cognitive Functionsmentioning

confidence: 99%

Longitudinal genetic studies of cognitive characteristics

et al. 2020

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The present review describes longitudinal studies of cognitive traits and functions determining the causes of their variations and their possible correction to prevent cognitive impairment. The present study reviews the involvement of such environmental factors as nutrition, prenatal maternal stress, social isolation and others in cognitive functioning. The role of epigenetic factors in the implementation of environmental effects in cognitive characteristics is revealed. Considering the epigenome significance, several studies were focused on the design of substances affecting methylation and histone modification, which can be used for the treatment of cognitive disorders. The appropriate correction of epigenetic factors related to environmental differences in cognitive abilities requires to determine the mechanisms of chromatin modifications and variations in DNA methylation. Transposons representing stress-sensitive DNA elements appeared to mediate the environmental influence on epigenetic modifications. They can explain the mechanism of transgenerational transfer of information on cognitive abilities. Recently, large-scale meta-analyses based on the results of studies, which identified genetic associations with various cognitive traits, were carried out. As a result, the role of genes actively expressed in the brain, such as BDNF, COMT, CADM2, CYP2D6, APBA1, CHRNA7, PDE1C, PDE4B, and PDE4D in cognitive abilities was revealed. The association between cognitive functioning and genes, which have been previously involved in developing psychiatric disorders (MEF2C, CYP2D6, FAM109B, SEPT3, NAGA, TCF20, NDUFA6 genes), was revealed, thus indicating the role of the similar mechanisms of genetic and neural networks in both normal cognition and cognitive impairment. An important role in both processes belongs to common epigenetic factors. The genes involved in DNA methylation (DNMT1, DNMT3B, and FTO), histone modifications (CREBBP, CUL4B, EHMT1, EP300, EZH2, HLCS, HUWE1, KAT6B, KMT2A, KMT2D, KMT2C, NSD1, WHSC1, and UBE2A) and chromatin remodeling (ACTB, ARID1A, ARID1B, ATRX, CHD2, CHD7, CHD8, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SRCAP, and SS18L1) are associated with increased risk of psychiatric diseases with cognitive deficiency together with normal cognitive functioning. The data on the correlation between transgenerational epigenetic inheritance of cognitive abilities and the insert of transposable elements in intergenic regions is discussed. Transposons regulate genes functioning in the brain due to the processing of their transcripts into non-coding RNAs. The content, quantity and arrangement of transposable elements in human genome, which do not affect changes in nucleotide sequences of protein encoding genes, but affect their expression, can be transmitted to the next generation.

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Section: Genetic Studies Of Cognitive Functionsmentioning

confidence: 99%

Longitudinal genetic studies of cognitive characteristics

et al. 2020

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“…Educational attainment captures cognitive ability but more broadly reflects personality, motivation, and perseverance. Multiple large-scale, genome-wide association studies have associated genetic variation in the gene encoding phosphodiesterase-4D (PDE4D) with biologic variation in educational attainment (Lam et al, 2017; Xu et al, 2017; Lee et al, 2018; Savage et al, 2018; Davies et al, 2019; Gurney, 2019). PDE4D is a key modulator of cAMP signaling within dendritic spines and thereby synaptic processes underlying short- and long-term forms of memory (Baumgärtel et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…PDE4D inhibitors have also been shown to improve memory function without causing significant emetic-like behavior in rodents (Bruno et al, 2011; Zhang et al, 2017). The large size of the PDE4D gene, and its complex pattern of promoter utilization and alternative splicing associates genetic variation in dimeric forms of the PDE4D enzyme with biologic variation in human cognitive function (Bender and Beavo, 2006; Gurney, 2019). The importance of dimeric forms of PDE4D for normal brain function is underscored by the discovery of PDE4D missense mutations in an ultrarare, neurodevelopmental disorder known as acrodysostosis type 2 with or without hormone resistance (Lee et al, 2012; Linglart et al, 2012; Michot et al, 2012; Lynch et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Protection from Amyloid β Peptide–Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor

Cui

Zhang

Zheng

et al. 2019

The Journal of Pharmacology and Experimental Therapeutics

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Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Ab 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Ab impairment. Microinjection of oligomeric Ab 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Ab-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brainderived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Ab-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Ab 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Ab 1-42 neurotoxicity.

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“…The development of therapeutic indications for Alzheimer’s Disease, Huntington’s disease, schizophrenia, depression and cognitive enhancement continues to be the subject of ongoing research 86,87 . Extensive discussion of PDE4D, previously discovered by large scale educational attainment GWAS, is reported elsewhere 88 . In the present study, improved eQTL mapping supports the nootropic function of inhibiting PDE4D.…”

Section: Discussionmentioning

confidence: 99%

Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics

Lam

Chen

Xia

et al. 2020

Preprint

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BackgroundCognitive traits demonstrate significant genetic correlations with many psychiatric disorders and other health-related traits. Many neuropsychiatric and neurodegenerative disorders are marked by cognitive deficits. Therefore, genome-wide association studies (GWAS) of general cognitive ability might suggest potential targets for nootropic drug repurposing. Our previous effort to identify “druggable genes” (i.e., GWAS-identified genes that produce proteins targeted by known small molecules) was modestly powered due to the small cognitive GWAS sample available at the time. Since then, two large cognitive GWAS meta-analyses have reported 148 and 205 genome-wide significant loci, respectively. Additionally, large-scale gene expression databases, derived from post-mortem human brain, have recently been made available for GWAS annotation. Here, we 1) reconcile results from these two cognitive GWAS meta-analyses to further enhance power for locus discovery; 2) employ several complementary transcriptomic methods to identify genes in these loci with variants that are credibly associated with cognition; and 3) further annotate the resulting genes to identify “druggable” targets.MethodsGWAS summary statistics were harmonized and jointly analysed using Multi-Trait Analysis of GWAS [MTAG], which is optimized for handling sample overlaps. Downstream gene identification was carried out using MAGMA, S-PrediXcan/S-TissueXcan Transcriptomic Wide Analysis, and eQTL mapping, as well as more recently developed methods that integrate GWAS and eQTL data via Summary-statistics Mendelian Randomization [SMR] and linkage methods [HEIDI], Available brain-specific eQTL databases included GTEXv7, BrainEAC, CommonMind, ROSMAP, and PsychENCODE. Intersecting credible genes were then annotated against multiple chemoinformatic databases [DGIdb, KI, and a published review on “druggability”].ResultsUsing our meta-analytic data set (N = 373,617) we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. 26 genes were associated with general cognitive ability via SMR, 16 genes via STissueXcan/S-PrediXcan, 47 genes via eQTL mapping, and 68 genes via MAGMA pathway analysis. The use of the HEIDI test permitted the exclusion of candidate genes that may have been artifactually associated to cognition due to linkage, rather than direct causal or indirect pleiotropic effects. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging on our various transcriptome and pathway analyses, as well as available chemoinformatic databases, we identified 16 putative genes that may suggest drug targets with nootropic properties.DiscussionResults converged on several categories of significant drug targets, including serotonergic and glutamatergic genes, voltage-gated ion channel genes, carbonic anhydrase genes, and phosphodiesterase genes. The current results represent the first efforts to apply a multi-method approach to integrate gene expression and SNP level data to identify credible actionable genes for general cognitive ability.

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Genetic Association of Phosphodiesterases With Human Cognitive Performance

Cited by 23 publications

References 62 publications

Longitudinal genetic studies of cognitive characteristics

Longitudinal genetic studies of cognitive characteristics

Protection from Amyloid β Peptide–Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor

Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics

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