Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

The lack of replication for many reported associations with longevity could be due, at least partly, to the use of different definitions for cases and controls between studies. Furthermore, even within a study, the use of a single age cut-off phenotype for men and women and for individuals belonging to different birth cohorts will give rise to heterogeneity, as survival probabilities differ by sex and birth cohort, and genetic effects are known to be age- and birth cohort-specific. In an attempt to mitigate the effects of heterogeneous case and control groups, we use country-, sex- and birth cohort-specific life tables to identify ages that correspond to different survival percentiles to define cases and controls in our meta-analyses of GWA studies of longevity. Furthermore, most studies in our meta-analyses use controls from the same study population as the cases, which limits the impact of sampling biases that could confound associations. The current meta-analyses include individuals from 20 cohorts from populations of European, East Asian, or African American descent. Two sets of cases are examined: individuals surviving at or beyond the age corresponding to the 90th survival percentile (90th percentile cases) or the 99th survival percentile (99th percentile cases) based on life tables specific to the country where each cohort was based, sex, and birth cohort (i.e., birth year). The same country-, sex-, and birth cohort-specific life tables are used to define the age threshold for controls, corresponding to the 60th percentile of survival. We identify two genome-wide significant loci, of which one is replicated in two independent European cohorts that use de novo genotyping. We also perform a gene-level association analysis based on tissue-specific gene expression and identify additional longevity genes. In addition, using linkage disequilibrium (LD) score regression, we show that longevity is genetically correlated with multiple diseases and traits.

Genome-wide association meta-analyses

We performed two meta-analyses in individuals of European ancestry combining cohort-specific genome-wide association data generated using 1000 Genomes imputation: 90th percentile cases versus all controls and 99th percentile cases versus all controls. 

The rare allele of this variant (A) was associated with lower odds of surviving to the 90th percentile age and there was no evidence of heterogeneity of effect across cohorts.

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