GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy
GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy
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DOI：
10.1093/gerona/glu166
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发表时间：
2015-01-01
影响因子：
5.1
通讯作者：
Murabito, Joanne M.
中科院分区：
文献类型：
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作者：
Broer, Linda;Buchman, Aron S.;Murabito, Joanne M.
背景据估计，基因对人类寿命的贡献在15%到25%之间。只有两个基因，APOE和FOXO 3，在多个独立的研究中显示与长寿相关。我们对全基因组关联研究进行了荟萃分析，包括6，036例长寿病例，年龄>= 90岁，以及3，757例年龄在55岁至80岁之间死亡的对照。我们还试图复制早期确定的单核苷酸多态性（SNP）与长寿的关联。在我们的荟萃分析中，我们发现了CADM 2（比值比[OR] = 0.81; p值= 9.66 x 10（-7））和GRIK 2（比值比= 1.24; p值= 5.09 x 10（-8））附近SNP与长寿相关的提示性证据。当试图复制早期在全基因组关联研究中发现的结果时，只有APOE基因座始终复制。在对候选基因FOXO 3的额外查找中，我们发现，当将已发表的数据纳入我们的荟萃分析时，一个早期发现的变异体显示出与长寿的高度显著相关性（优势比= 1.17; p值= 1.85 x 10（-10））。我们没有发现新的全基因组与长寿的显著关联，也没有复制除了APOE和FOXO 3之外的早期发现。我们无法找到与生存年龄>= 90岁的新关联，因为长寿代表了具有异质性遗传基础的多种复杂性状，或者，长寿可能受到标准全基因组基因分型和常见变异归因未捕获的罕见变异的调节。
Background. The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.Methods. We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age >= 90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.Results. In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 x 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 x 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85 x 10(-10)).Conclusions. We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages >= 90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.