Article

Genetic Variants Influencing Human Longevity from Late-Onset Alzheimer’s Disease (LOAD) Genome-Wide Association Studies (GWAS)

Human Genetics, School of Molecular Medical Science, University of Nottingham, Nottingham, UK.
Neurobiology of aging (Impact Factor: 4.85). 03/2012; 33(8):1849.e5-18. DOI: 10.1016/j.neurobiolaging.2012.02.014
Source: PubMed

ABSTRACT Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 × 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.

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    • "The recent finding by two large consortiums that a rare variant of TREM2, a gene which regulates phagocytosis and the activation state of microglia/macrophages, is linked to LOAD has further highlighted the important role of innate immunity in AD. This finding adds to prior data linking other genes that are associated with microglia function and a low increased risk of LOAD, such as CR1, CD33, and MS4A4A/MS4A6A [96]. These studies indicate that modification of microglial function in AD is an important therapeutic target. "
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    International Journal of Cell Biology 10/2013; 2013:576383. DOI:10.1155/2013/576383
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    • "The last several decades of research have yielded only 1 genetic risk factor of large effect for late-onset AD (LOAD)dapolipoprotein- E (APOE)dwith 2 copies of the ε4 allele conferring approximately 6- to 30-fold risk for the disease (Akiyama et al., 1993). More recent genome-wide association studies (GWAS) have identified and replicated 9 additional AD susceptibility genes, including BIN1, CLU, ABCA7, CR1, PICALM, MS4A6A, CD33, MS4A4E, and CD2AP (Belbin et al., 2011; Carrasquillo et al., 2011; Harold et al., 2009; Hollingworth et al., 2011; Naj et al., 2011; Shi et al., 2012). However, all of these have low effect sizes (odds ratios of 0.87e1.23) "
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    Neurobiology of aging 10/2012; 34(5). DOI:10.1016/j.neurobiolaging.2012.09.020 · 4.85 Impact Factor
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    • "However, this year it was published a study where the 10 most promising late-onset AD susceptibility genes identified through several recent large GWAS (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1). This study has been identified curiously, apart from the APOE locus which showed compelling evidence of association with risk on human life span, none of the other gene loci demonstrated significant evidence of association (Shi et al., 2012). However, last studies of Carro's group demonstrated three new polymorphisms in the genes PLA2G3, IGF-I and LRP2 associated with AD in a Spanish population (Martínez-García et al., 2010; Vargas et al., 2010b, 2011). "
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