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Lorna M Lopez,
Sarah E Harris,
Michelle Luciano,
Dave Liewald,
Gail Davies,
Alan J Gow,
Albert Tenesa,
Antony Payton,
Xiayi Ke,
Lawrence J Whalley, Helen Fox,
Paul Haggerty,
William Ollier,
Andrew Pickles,
David J Porteous,
Michael A Horan,
Neil Pendleton,
John M Starr,
Ian J Deary
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ABSTRACT: Genetic influences have an important role in the ageing process. The genetic factors that influence success in bodily ageing may also contribute to the successful ageing of cognitive abilities. A comparative genomics approach found longevity genes conserved between yeast Saccharomyces cerevisiae and nematode Caenorhabditis elegans. We hypothesised that these longevity genes influence variance in cognitive ability and age-related cognitive decline in humans. Here, we investigated six of these genes that have human orthologs and show expression in the brain. We tested AFG3L2 (MIM: 604581, AFG3 ATPase family gene 3-like 2 (yeast)), FRAP1 (MIM: 601231, a FK506 binding protein 12-rapamycin associated protein), MAT1A, MAT2A (MIM: 610550 and 601468, methionine adenosyltransferases I alpha and II alpha, respectively), SYNJ1 and SYNJ2 (MIM: 604297 and 609410, synaptojanin-1 and synaptojanin-2, respectively) in approximately 1000 healthy older Scots: the Lothian Birth Cohort 1936 (LBC1936). They were tested on general cognitive ability at age 11 years. At a mean age of 70 years, they re-sat the same general cognitive ability test and underwent an additional battery of diverse cognitive tests. In all, 70 tag and functional SNPs in the six longevity genes were genotyped and tested for association with cognition and cognitive ageing in LBC1936. Suggestive associations were detected between SNPs in SYNJ2, MAT1A, AFG3L2 and SYNJ1 and a general memory factor and general cognitive ability at age 11 and 70 years. Replication studies for cognitive ability associations were performed in 2506 samples from the Cognitive Ageing Genetics in England and Scotland consortium. A meta-analysis replicated the SYNJ2 association with cognitive abilities (lowest P=0.00077). SYNJ2 is a novel gene in which variation is potentially associated with cognitive abilities.
European journal of human genetics: EJHG 11/2011; 20(3):341-7. · 3.56 Impact Factor
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ABSTRACT: Dopaminergic systems contribute to individual differ-ences in cognitive ability (Savitz et al., 2006). However, the relationship between dopamine concentrations and cognition is nonlinear. Beyond its actions as a neuro-transmitter within the brain, dopamine and its metabo-lites are hypothesized to have cytotoxic actions on neurons (Weingarten and Zhou, 2001). Pathways that facilitate the disposal of intracellular dopamine include oxidative deamination by monoamine oxidase-A, seques-tration into synaptic vesicles by vesicular monoamine transporter and metabolism of autooxidized products of dopamine by macrophage migration inhibitory factor and glutathione-S-transferases (GST) (Weingarten and Zhou, 2001). An alternative hypothesis to explain the 'inverted-U' relationship between dopamine levels and cognition is that at high levels dopamine become neurotoxic. We hypothesized, because cognitive impairment is associated with high dopamine concentrations, that genetic variation in dopamine metabolism contribute to cognitive ability. GSTz1 is a candidate gene because its functional polymorphism affects dopamine metabolism (Fang et al., 2006). We applied repeated measures mixed general linear modelling over three cognitive assessments comprising Mini-Mental State Examination (a general cognitive screening test), Raven's Progressive Matrices (a measure of nonverbal reasoning), Rey Auditory Verbal Learning Test (a measure of verbal declarative memory), Wechsler Adult Intelligence Scale subtests Block Design (a measure of visuo-spatial ability) and Digit Symbol coding (a measure of processing speed), and Uses of Common Objects Test (a measure of executive function) between ages 64 and 68 years in a cohort of 470 community volunteers from the 1947 Scottish Mental Survey resident in the Aberdeen area with validated childhood intelligence quotient (IQ) data (Starr et al., 2007) whose GSTz1-1002 G > A polymorphism was known. The sample did not differ significantly from the Hardy–Weinberg equilibrium (w 2 = 0.18, NS). In view of the small number of A/A homozygotes, participants were designated as A-carriers or noncarriers as an independent variable in analyses with cognitive outcomes. No significant difference was observed between GSTz1 A-carriers and noncarriers in age 11 IQ scores (F = 0.23, P = 0.63, carriers mean: 99.8, noncarriers mean: 100.8). GSTz1 was significantly associated with the underlying cognitive trait at age 64–68 years (F = 5.27, P = 0.022) with A-carriers having a lower mean estimated marginal mean score across all six tests over the three waves of 34.1 (95% confidence intervals: 33.3–34.9) compared with noncarriers, mean of 35.1 (95% confidence intervals: 34.8–35.4); this score represents a virtual mean score with the six cognitive tests weighted equally and after adjustment for wave and age 11 IQ. A trend was observed toward a greater effect on verbal memory (F = 2.06, P = 0.068), but no significant effect of GSTz1 on change in cognitive ability over time (F = 0.60, P = 0.55). GSTz1 SNP-1002 G > A is associated with relative impairment of cognitive ability in this sample aged 64–68 years. Mean scores across all six cognitive tests over the three waves of testing for A-carriers were about 3% lower than mean scores for noncarriers. The results are consistent with the hypothesis that reduced disposal of dopamine and its autooxidized metabolites have an adverse effect on cognition and that this may reflect a neurotoxic rather than a neurotransmission effect. The results are consistent with the hypothesis that reduced dopamine metabolism adversely affects cogni-tion. Future studies should consider neurotoxic as well as neurotransmission effects of dopamine.
Psychiatric genetics 08/2008; 18(4):211-2. · 2.33 Impact Factor
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ABSTRACT: Dopaminergic neurotransmission in the pre-frontal cortex (PFC) contributes to individual cognitive differences in animals and humans. Catechol-O-methyltransferase (COMT) influences dopamine concentration in the PFC. Functional variation in the human COMT gene occurs at a single nucleotide polymorphism (SNP)--472G>A--that results in a valine (Val) to methionine (Met) amino acid substitution (Val158Met). The Met/Met form is less active resulting in higher dopamine concentrations and thus may enhance cognitive function. We applied repeated measures mixed general linear modelling over three waves between ages 64 and 68 years to optimise cognitive phenotype characterisation in a cohort of 473 community volunteers who had validated childhood IQ data. After adjusting for childhood IQ, wave of testing and specific test type, COMT Val158Met genotype polymorphism had a significant overall effect on cognition (F(2,935.7)=7.92, p<.001) with adjusted means of all cognitive test scores taken together being: Val/Val 33.0 (95% C.I. 32.2-33.8), Val/Met 34.9 (95% C.I. 34.3-35.5), and Met/Met 34.9 (95% C.I. 34.1-35.8). This study adds to the evidence that the Val/Val polymorphism has a detrimental effect on cognition, extending upwards the age range in which such an effect has been detected.
Neuroscience Letters 07/2007; 421(1):57-61. · 2.11 Impact Factor
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Nitzan Mekel-Bobrov,
Danielle Posthuma,
Sandra L Gilbert,
Penelope Lind,
M Florencia Gosso,
Michelle Luciano,
Sarah E Harris,
Timothy C Bates,
Tinca J C Polderman,
Lawrence J Whalley, [......],
Patrick D Evans,
Grant W Montgomery,
Croydon Fernandes,
Peter Heutink,
Nicholas G Martin,
Dorret I Boomsma,
Ian J Deary,
Margaret J Wright,
Eco J C de Geus,
Bruce T Lahn
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ABSTRACT: Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary microcephaly, a developmental disorder characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid condition. This has led to the hypothesis that the adaptive evolution of these genes has contributed to the emergence of modern human cognition. As with other candidate loci, however, this hypothesis remains speculative due to the current lack of methodologies for characterizing the evolutionary function of these genes in humans. Two primary microcephaly genes, ASPM and Microcephalin, have been implicated not only in the adaptive evolution of the lineage leading to humans, but in ongoing selective sweeps in modern humans as well. The presence of both the putatively adaptive and neutral alleles at these loci provides a unique opportunity for using normal trait variation within humans to test the hypothesis that the recent selective sweeps are driven by an advantage in cognitive abilities. Here, we report a large-scale association study between the adaptive alleles of these genes and normal variation in several measures of IQ. Five independent samples were used, totaling 2393 subjects, including both family-based and population-based datasets. Our overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype.
Human Molecular Genetics 04/2007; 16(6):600-8. · 7.64 Impact Factor
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ABSTRACT: Non-pathological cognitive ageing is a distressing condition affecting an increasing number of people in our 'ageing society'. Oxidative stress is hypothesised to have a major role in cellular ageing, including brain ageing.
Associations between cognitive ageing and 325 single nucleotide polymorphisms (SNPs), located in 109 genes implicated in oxidative stress and/or cognition, were examined in a unique cohort of relatively healthy older people, on whom we have cognitive ability scores at ages 11 and 79 years (LBC1921). SNPs showing a significant positive association were then genotyped in a second cohort for whom we have cognitive ability scores at the ages of 11 and 64 years (ABC1936). An intronic SNP in the APP gene (rs2830102) was significantly associated with cognitive ageing in both LBC1921 and a combined LBC1921/ABC1936 analysis (p < 0.01), but not in ABC1936 alone.
This study suggests a possible role for APP in normal cognitive ageing, in addition to its role in Alzheimer's disease.
BMC Genetics 02/2007; 8:43. · 2.47 Impact Factor
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ABSTRACT: The relationship between blood pressure and cognition in old age remains unclear. Some data indicate that elevated blood pressure causes cognitive deficits whilst others show that lower early life mental ability predicts high blood pressure in adulthood. Longitudinal studies in which mental ability earlier in life is known are needed to clarify the relationship.
To measure the effect of blood pressure on cognition in late adulthood after adjusting for early life mental ability.
The sample comprised survivors of the 1947 Scottish Mental Survey who had validated IQ scores at age 11. Six cognitive tests - Mini-Mental State Examination, Raven's Progressive Matrices, Rey Auditory Verbal Learning Test, Uses of Common Objects Test, Digit Symbol Test and Block Design - were administered at ages 64, 66 and 68 years. Sitting and standing blood pressure was also measured at each wave of follow-up. Mixed general linear models were constructed with each cognitive test treated as a repeated measure of an underlying cognitive trait and with wave of testing also set as a repeated measure. Mental ability at age 11 was entered as a covariate.
504 participants were tested at wave 1 with 368 returning at wave 2 and 300 at wave 3. Age 11 mental ability did not predict any of the blood pressure measures. There were several significant associations between blood pressure variables and cognitive test scores in univariate models. After adjusting for significant effects of wave of testing, type of cognitive test, the interaction between these, age 11 mental ability, age, gender and occupation in a multivariate model, the main effect of BP trait was no longer significant (p = 0.44) nor its effect over time (p = 0.26), though there was a significant interaction between blood pressure trait (BP) and test type with a distinctly negative effect of BP on Auditory Verbal Learning Test (p = 0.007, -0.13 points per mm Hg higher, 95% CI -0.22 to -0.033).
The effects of blood pressure on cognition in old age are finely nuanced. Multivariate repeated measures models reveal a differential effect of blood pressure on verbal recall.
Gerontology 02/2007; 53(6):432-7. · 2.78 Impact Factor
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ABSTRACT: Abstract
Background
Non-pathological cognitive ageing is a distressing condition affecting an increasing number of people in our 'ageing society'. Oxidative stress is hypothesised to have a major role in cellular ageing, including brain ageing.
Results
Associations between cognitive ageing and 325 single nucleotide polymorphisms (SNPs), located in 109 genes implicated in oxidative stress and/or cognition, were examined in a unique cohort of relatively healthy older people, on whom we have cognitive ability scores at ages 11 and 79 years (LBC1921). SNPs showing a significant positive association were then genotyped in a second cohort for whom we have cognitive ability scores at the ages of 11 and 64 years (ABC1936). An intronic SNP in the APP gene (rs2830102) was significantly associated with cognitive ageing in both LBC1921 and a combined LBC1921/ABC1936 analysis ( p < 0.01), but not in ABC1936 alone.
Conclusion
This study suggests a possible role for APP in normal cognitive ageing, in addition to its role in Alzheimer's disease.
BMC Genetics. 01/2007;
