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Edinburgh Research Explorer Edinburgh Research Explorer A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition Citation for published version: Harris, SE, Fox, H, Wright, AF, Hayward, C, Starr, J, Whalley, LJ & Deary, IJ 2007, 'A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition', BMC Genetics, vol. 8, 43, pp. -. https://doi.org/10.1186/1471-2156-8-43 Digital Object Identifier (DOI): 10.1186/1471-2156-8-43 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: BMC Genetics Publisher Rights Statement: ©Harris, S. E., Fox, H., Wright, A. F., Hayward, C., Starr, J., Whalley, L. J., & Deary, I. J. (2007). A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition. BMC Genetics, 8, -[43]doi: 10.1186/1471-2156-8-43 General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 30. Sep. 2021 BMC Genetics BioMed Central Research article Open Access A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition Sarah E Harris1, Helen Fox2, Alan F Wright3, Caroline Hayward3, John M Starr4, Lawrence J Whalley2 and Ian J Deary*1 Address: 1Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK, 2Department of Mental Health, University of Aberdeen, Clinical Research Centre, Royal Cornhill Hospital, Cornhill Road, Aberdeen, AB25 2ZH, UK, 3Medical Research Council Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK and 4Department of Geriatric Medicine, University of Edinburgh, Royal Victoria Hospital, Craigleith Road, Edinburgh EH4 2DN, UK Email: Sarah E Harris - [email protected]; Helen Fox - [email protected]; Alan F Wright - [email protected]; Caroline Hayward - [email protected]; John M Starr - [email protected]; Lawrence J Whalley - [email protected]; Ian J Deary* - [email protected] * Corresponding author Published: 2 July 2007 Received: 31 January 2007 Accepted: 2 July 2007 BMC Genetics 2007, 8:43 doi:10.1186/1471-2156-8-43 This article is available from: http://www.biomedcentral.com/1471-2156/8/43 © 2007 Harris et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. Background change, the majority of the between-individual variation Individuals differ in their cognitive skills, and in how is accounted for by a common factor of general cognitive much these cognitive skills change as people grow older. ability (or g)[2,3]. Both mild intellectual impairment (low That is, there are individual differences in the trait (or trait intelligence) and accelerated age-related cognitive level) of intelligence, and in the age-related change (or tra- decline (increased downward trajectory in intelligence) jectory). We have previously shown that about 50% of the have a major impact on society, because of the large variance in trait intelligence is stable from the age of 11 to number of individuals involved who have limited inde- the age of 79[1]. In both the trait and the age-related pendence. In our increasingly 'ageing society', disabilities Page 1 of 18 (page number not for citation purposes) BMC Genetics 2007, 8:43 http://www.biomedcentral.com/1471-2156/8/43 linked to cognitive ageing are a growing medical and both brain regions, gene expression profiles showed social problem. increased inflammatory response and oxidative stress gene expression in the older mice. These authors con- There are environmental and genetic contributions to cluded that oxidative stress is an important and perhaps individual differences in trait intelligence and cognitive underlying cause of the ageing process in post-mitotic ageing[4,5]. Genetic influences account for more than (neural) tissues. In a similar study, Jiang et al[29] probed 50% of the variability in adult cognitive abilities[6]. We over 11,000 genes in cortex and hypothalamus in 2 have shown that genetic variation in some specific genes, month and 22 month old mice and found altered expres- e.g. APOE is associated with change in cognitive ability sion for 98 genes (0.9%) in cortex, about 20% of which with age, but not with the stable trait of intelligence[7]. were also altered in hypothalamus. Significant changes (at Therefore, it is likely that some genetic variants are associ- least two-fold) were found in a variety of proteins, includ- ated with life-long cognitive abilities and others specifi- ing eight concerned with oxidative stress response. cally with variance in age-related cognitive decline. The search for genetic contributions to cognitive ageing can be We previously identified associations between common guided by focussing on mechanisms that affect brain age- functional polymorphisms in genes involved in AD or ing[5]. oxidative stress and cognitive ageing[7,30,31]. However, these studies all involved genotyping small numbers of Oxidative stress is hypothesised to be a significant con- polymorphisms in a small sample of genes. Technology is tributor to cellular ageing. The free radical theory of age- now available to genotype easily much larger numbers of ing predicts that, with increasing age, free radicals, reactive polymorphisms. The aim of the present study was to by-products of oxidative metabolism, damage macromol- investigate the influence of genetic variation in genes pri- ecules such as DNA, protein and lipids[8,9]. Support for marily related to oxidative stress and antioxidant defences the free radical hypothesis of ageing comes from a wide in two cohorts of relatively healthy older individuals. variety of sources, including analyses of mutations and These are the Lothian Birth Cohort of 1921 (LBC1921) transgenic animals (for recent reviews see[10,11]). The and the Aberdeen Birth Cohort of 1936 (ABC1936), on brain is particularly vulnerable to oxidative damage as a whom cognitive ability test scores are available at age 11 result of its high aerobic metabolism and high concentra- and in later life; that is, they have data on the lifetime trait tions of polyunsaturated fatty acids that are susceptible to of intelligence, and lifetime cognitive change[32]. These lipid peroxidation [12-15]. cohorts form a unique resource to test for genes associated with cognitive ageing. Both cohorts took an identical Oxidative damage to mitochondrial DNA accumulates at mental ability test at age 11 and a different but overlap- a ten-fold higher rate than nuclear DNA, although its pre- ping series of cognitive ability tests at either age 79 cise significance to ageing remains controversial[16,17]. (LBC1921) or age 64 (ABC1936)[32]. To utilise this The constant leak of reactive oxygen species from mito- resource a candidate gene genetic association study was chondria increases with age, and deficiency of both mito- performed by genotyping 387 SNPs in 444 members of chondrial and cytoplasmic superoxide dismutase are LBC1921. We have ~80% power to detect an effect size of associated with neurodegeneration due to oxidative dam- 3% at a type-1 error rate of 0.01. Replication of possible age [18-20]. A role for oxidative stress has been proposed associations is important. Therefore, SNPs that showed a both in Alzheimer's disease (AD), associated with amy- positive association with either cognitive ability at age 11 loid plaques[21,22], and in Parkinson's disease, with the or cognitive ageing were then genotyped in 485 members presence of iron and auto-oxidised monoamines[23]. A of ABC1936. role for oxidative stress has also been proposed in mild cognitive impairment[24,25]. Non-pathological cognitive Results ageing was found to be related to differences in oxidative 384 SNPs were selected for genotyping by the Golden- stress (measured, for example, by thiobarbituric acid reac- Gate™ assay. A multiplex assay was successfully designed tive substances) in a large community study of older peo- for 322 SNPs (83.9%).
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