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A meta-analysis of genome-wide association studies identifies multiple longevity genes

human longevity genome wide association gwa meta-analyses

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#1 Engadin

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Posted 14 August 2019 - 03:44 PM


SOURCE: nature

 

 

 

ABSTRACT

 

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.

 

 

INTRODUCTION

 

The average human life expectancy has been increasing for centuries1. Based on twin studies, the heritability of human lifespan has been estimated to be ~25%, although this estimate differs among studies2. On the other hand, the heritability of lifespan based on the correlation of the mid-parent (i.e., the average of the father and mother) and offspring difference between age at death and expected lifespan was estimated to be 12%3. A recent study has indicated that the different heritability estimates may be inflated due to assortative mating, leaving a true heritability that is below 10%4. The heritability of lifespan, estimated using the sibling relative risk, increases with age5 and is assumed to be enriched in long-lived families, particularly when belonging to the 10% longest-lived of their generation6. To identify genetic associations with human lifespan, several genome-wide association (GWA) studies have been performed7,8,9,10,11,12,13,14,15,16,17,18,19,20. These studies have used a discrete (i.e., older cases versus younger controls) or a continuous phenotype (such as age at death of individuals or their parents). The selection of cases for the studies using a discrete longevity phenotype has been based on the survival to ages above 90 or 100 years or belonging to the top 10% or 1% of survivors in a population. Studies defining cases using a discrete longevity phenotype often need to rely on controls from more contemporary birth cohorts, because all others from the case birth cohorts have died before sample collection. Previous GWA studies have identified several genetic variants, but the only locus that has shown genome-wide significance (P ≤ 5 × 10−8) in multiple independent meta-analyses of GWA studies is apolipoprotein E (APOE)21, where the ApoE ε4 variant is associated with lower odds of being a long-lived case.

 

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 cohort22, and genetic effects are known to be age- and birth cohort-specific5,23. 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 regression24, we show that longevity is genetically correlated with multiple diseases and traits.

 

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Also tagged with one or more of these keywords: human longevity, genome wide association, gwa, meta-analyses

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