ABSTRACT
The liver X receptor agonist, GW3965, improves cognition in Alzheimer's disease (AD) mouse models. Here, we determined if short-term GW3965 treatment induces changes in the DNA methylation state of the hippocampus, which are associated with cognitive improvement. Twenty-four-month-old triple-transgenic AD (3xTg-AD) mice were treated with GW3965 (50 mg/kg/day for 6 days). DNA methylation state was examined by modified bisulfite conversion and hybridization on Illumina Infinium Methylation BeadChip 450 k arrays. The Morris water maze was used for behavioral analysis. Our results show in addition to improvement in cognition methylation changes in 39 of 13,715 interrogated probes in treated 3xTg-AD mice compared with untreated 3xTg-AD mice. These changes in methylation probes include 29 gene loci. Importantly, changes in methylation status were mainly from synapse-related genes (SYP, SYN1, and DLG3) and neurogenesis-associated genes (HMGB3 and RBBP7). Thus, our results indicate that liver X receptors (LXR) agonist treatment induces rapid changes in DNA methylation, particularly in loci associated with genes involved in neurogenesis and synaptic function. Our results suggest a new potential mechanism to explain the beneficial effect of GW3965.
Subject(s)
Alzheimer Disease/metabolism , Benzoates/pharmacology , Benzylamines/pharmacology , DNA Methylation/drug effects , Neurogenesis , Orphan Nuclear Receptors/agonists , Synapses/drug effects , Alzheimer Disease/genetics , Animals , Female , HMGB3 Protein/genetics , HMGB3 Protein/metabolism , Liver X Receptors , Mice , Qa-SNARE Proteins/genetics , Qa-SNARE Proteins/metabolism , Retinoblastoma-Binding Protein 7/genetics , Retinoblastoma-Binding Protein 7/metabolism , Synapses/metabolism , Synaptophysin/genetics , Synaptophysin/metabolismSubject(s)
Parkinson Disease/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Ubiquitin Thiolesterase/genetics , alpha-Macroglobulins/genetics , Age of Onset , Aged , Alleles , Brain-Derived Neurotrophic Factor/genetics , Catechol O-Methyltransferase/genetics , Colombia/epidemiology , Dopamine Plasma Membrane Transport Proteins/genetics , Female , Genetic Markers , Genotype , Humans , Male , Middle Aged , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic , tau Proteins/geneticsABSTRACT
BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is an important psychiatric condition in terms of its prevalence and impact on quality of life. It has one of the highest heritabilities found in psychiatric disorders. A number of association studies exploring several candidate genes in different populations around the world have been carried out. The objective of the present study was to carry out a meta-analysis for 8 common variants located in 5 top candidate genes for ADHD (BDNF, HTR1B, SLC6A2, SLC6A4 and SNAP25); these genes are known to be involved in synaptic transmission and plasticity. METHODS: We performed a search for published genetic association studies that analyzed the candidate polymorphisms in different populations, and we applied state-of-the-art meta-analytical procedures to obtain pooled odds ratios (ORs) and to evaluate potential basis of heterogeneity. We included 75 genetic association studies in these meta-analyses. RESULTS: A major part of the previously postulated associations were nonconsistent in the pooled odds ratios. We observed a weak significant association with a single nucleotide polymorphism (SNP) located in the 3' UTR region of the SNAP25 gene (rs3746544, T allele, OR 1.15, 95% confidence interval 1.01-1.31, p = 0.028, I(2) = 0%). In addition to the low coverage of genetic variability given by these variants, phenotypic heterogeneity between samples (ADHD subtypes, comorbidities) and genetic background may explain these differences. LIMITATIONS: Limitations of our study include the retrospective nature of our meta-analysis with the incorporation of study-level data from published articles. CONCLUSION: To our knowledge, the present study is the largest meta-analysis carried out for ADHD genetics; previously proposed cumulative associations with common polymorphisms in SLC6A4 and HTR1B genes were not supported. We identified a weak consistent association with a common SNP in the SNAP25 gene, a molecule that is known to be central for synaptic transmission and plasticity mechanisms.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Genetic Predisposition to Disease , Genetic Variation , Neuronal Plasticity/genetics , 3' Untranslated Regions , Brain-Derived Neurotrophic Factor/genetics , Databases, Genetic , Genome-Wide Association Study , Genotype , Humans , Norepinephrine Plasma Membrane Transport Proteins/genetics , Odds Ratio , Phenotype , Polymorphism, Single Nucleotide , Receptor, Serotonin, 5-HT1B/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Software , Synaptosomal-Associated Protein 25/geneticsABSTRACT
BACKGROUND: Genetic analysis of human longevity may be useful for the understanding of molecular mechanisms implicated in age-related diseases. The molecular genetics of human longevity is largely unexplored in Latin American populations and other developing countries. METHODS: To explore the possibility of an association of common polymorphisms in two candidate genes and longevity in Colombia, we analyzed two polymorphisms in apolipoprotein E (APOE) and angiotensin-converting enzyme (ACE) genes in a sample of 538 Colombian subjects (18-106 years), using previously validated PCR-based methodologies. RESULTS: We found a significant decrease in ACE DD genotype (24 vs. 16%) between young and old subject groups (mean age: 45 vs. 77 years) (p = 0.03). The ACE DD genotype and D allele decrease was significant only in women. There were no differences for APOE polymorphism between young and old subjects. CONCLUSIONS: Our results are compatible with the expected age-related decrease of ACE DD genotype. Future studies examining functional single nucleotide polymorphisms (SNPs) in the ACE gene and its correlation with serum ACE activity in the older subjects and their younger relatives in this sample are warranted.