CHRNA4
Neuronal acetylcholine receptor subunit alpha-4 precursor [NACRA4]
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To test the hypothesis that single nucleotide polymorphisms (SNPs) in DNA repair genes are associated with cognitive performance during normal aging, the relationship between SNPs in selected exons in DNA base excision repair (BER) genes and cognitive performance was examined in 712 healthy Norwegian individuals aged 20-75 years. SNPs examined included PolB(Pro242Arg), hOGG1(Ser326Cys), MutYH (Met22Val), MutYH(His324Gln), APE1(Gln51His), APE1(Glu148Asp), XRCC1(Lys298Asn), XRCC1(Arg7Leu), NEIL1(Asp252Asn), and NEIL2(Arg257Leu). XRCC1(Arg7Leu) and PolB(Pro242Arg) were characterized by single nucleotide variations (≤0.1% homozygote SNPs). hOGG1(Ser326Cys) (Ser/Cys 40.8%/Cys/Cys 5.7%), MutYH(His324Gln) (His/Gln37%/Gln/Gln 6.0%) and APE1(Glu148Asp) (Glu/Asp 51.3%/Asp/Asp 23.0%) were characterized by higher SNP frequencies. MutYH(Met22Val), APE1(Gln51His) and NEIL2(Arg257Leu) occurred at intermediate SNP frequencies of 11.5, 7.6 and 5.3%, respectively. Interestingly, hOGG1(Ser326Cys) and APE1(Gln51His) had genotype by age interactions with general cognitive function, reasoning, control and speed of processing in cross-sectional analysis and a significant effect on longitudinal decline. Dispersed association effects involving MutYH(His324Gln), MutYH(Met22Val), PolB(Pro242Arg) and NEIL2(Arg257Leu) were also detected when APOE or CHRNA4, were included in the statistical model, a result consistent with proposed involvement of the latter markers in human cognitive decline and/or function. In summary, the results support the notion that polymorphisms in BER genes modulate cognitive performance in healthy elderly individuals.
MeSH Terms
- Adult
- Aged
- Aging
- Biomarkers
- Cognition
- Cross-Sectional Studies
- DNA Repair
- Female
- Humans
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
Cholinergic influences on attention are well documented and recent evidence indicates that genetic variation in the alpha4beta2 nicotinic receptor affects attentional networks of the brain. Several behavioral and electrophysiological studies have shown that a common polymorphism in the CHRNA4 gene (rs1044396) affects aspects of visual and auditory attentional processing. We examined genetic effects on neuropsychological measures of memory and attention in an adult life-span sample (N=488). TT homozygotes perform speed and attention tasks more slowly than TC or CC allele carriers, with stronger effects on complex attention tasks in participant 70-79 years of age. There are no parallel effects on memory function. The results are consistent with clinical studies indicating that reduction in nicotinic receptor efficiency affects attention and speed, but not memory. Both normal age-related changes in receptor function and incipient pathology may have contributed to the results.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Attention
- Female
- Humans
- Male
- Memory
- Middle Aged
- Neuropsychological Tests
- Polymorphism, Single Nucleotide
- Psychomotor Performance
- Receptors, Nicotinic
- Young Adult
We investigated the relation between the two systems of visuospatial attention and working memory by examining the effect of normal variation in cholinergic and noradrenergic genes on working memory performance under attentional manipulation. We previously reported that working memory for location was impaired following large location precues, indicating the scale of visuospatial attention has a role in forming the mental representation of the target. In one of the first studies to compare effects of two single nucleotide polymorphisms (SNPs) on the same cognitive task, we investigated the neurotransmission systems underlying interactions between attention and memory. Based on our previous report that the CHRNA4 rs#1044396 C/T nicotinic receptor SNP affected visuospatial attention, but not working memory, and the DBH rs#1108580 G/A noradrenergic enzyme SNP affected working memory, but not attention, we predicted that both SNPs would modulate performance when the two systems interacted and working memory was manipulated by attention. We found the scale of visuospatial attention deployed around a target affected memory for location of that target. Memory performance was modulated by the two SNPs. CHRNA4 C/C homozygotes and DBH G allele carriers showed the best memory performance but also the greatest benefit of visuospatial attention on memory. Overall, however, the CHRNA4 SNP exerted a stronger effect than the DBH SNP on memory performance when visuospatial attention was manipulated. This evidence of an integrated cholinergic influence on working memory performance under attentional manipulation is consistent with the view that working memory and visuospatial attention are separate systems which can interact.
MeSH Terms
- Adolescent
- Aged
- Aging
- Attention
- Cues
- Discrimination, Psychological
- Dopamine beta-Hydroxylase
- Female
- Genetic Variation
- Humans
- Male
- Memory, Short-Term
- Polymorphism, Single Nucleotide
- Receptors, Nicotinic
- Recognition, Psychology
- Reference Values
- Space Perception
- Young Adult
In the present study, we investigated age-related changes in interactions between efficiency of neuronal repair mechanisms and efficiency of cholinergic neurotransmission in the context of attentional orienting. In addition, we explored white matter volume changes as possible neuronal underpinnings. A sample of 230 healthy middle-aged (53-64 years) and older (65-75 years) adults was genotyped for polymorphisms of APOE and CHRNA4, a nicotinic receptor subunit gene. Participants were administered a visuospatial attention task involving letter discrimination with location cues of varying validity. Genotype effects on white matter volume were also investigated in a subset of participants who received MRI scans. APOE interacted with CHRNA4, such that APOE-epsilon4 carriers who were also CHRNA4 TT homozygotes showed disproportionately slowed reaction time (RT) following invalid location cues. The interaction was stronger in the middle-aged participants than in the older participants. There was also a trend for individuals with combined APOE-epsilon4/CHRNA4 TT genotypes to show both lower white matter volume and slower overall RT on the attention task The interaction of a neurotransmission gene (CHRNA4) and a susceptibility gene (APOE) suggests that the efficiency of neuronal repair mechanisms may modulate the cholinergic system to influence attentional function.
MeSH Terms
- Aged
- Aging
- Analysis of Variance
- Apolipoprotein E4
- Apolipoproteins E
- Attention
- Brain
- Cues
- Discrimination, Psychological
- Female
- Genotype
- Humans
- Male
- Middle Aged
- Neuropsychological Tests
- Pattern Recognition, Visual
- Photic Stimulation
- Polymorphism, Genetic
- Reaction Time
- Receptors, Nicotinic