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

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.

PNPLA3 Genotype and Risk of Liver and All‐Cause Mortality

“…First, the variant has not been implicated in any of the largescale genome-wide association studies on mortality or parental life span that have been performed in recent years. (9) Second, if the M variant confers an increased mortality rate, one might expect it to be relatively depleted in older individuals, in turn causing frequencies of II, IM, and MM genotypes to diverge from those expected (i.e., violation of Hardy-Weinberg equilibrium). PNPLA3 p.I148M genotypes have been in Hardy-Weinberg equilibrium in several large cohorts, (10) again arguing against an effect on mortality.…”

“…Why is it surprising that PNPLA3 p.I148M associates with increased all‐cause mortality? First, the variant has not been implicated in any of the large‐scale genome‐wide association studies on mortality or parental life span that have been performed in recent years . Second, if the M variant confers an increased mortality rate, one might expect it to be relatively depleted in older individuals, in turn causing frequencies of II, IM, and MM genotypes to diverge from those expected (i.e., violation of Hardy‐Weinberg equilibrium).…”

Origin and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages

“…While the association between ApoE and recent arrival seems to be at odds with the higher level of ApoE expression by female peritoneal macrophages, ApoE expression may also be controlled partly by estrogen, as the Apoe gene contains an estrogen response element, and its expression is reduced in inflammatory peritoneal macrophages by macrophage-specific deletion of the estrogen receptor alpha 35 . Understanding how ApoE expression is regulated by tissue-residency and hormonal control may be important in many diseases in which is it is a known genetic risk factor and that exhibit strong sex-biases in risk, such as Alzheimer’s and cardiovascular disease 60 , but also in healthy aging where APOE variants are among the strongest predictors of human longevity 61 .…”

Longevity Relatives Count score identifies heritable longevity carriers and suggests case improvement in genetic studies

“…However, many of the identified loci could not be replicated in independent studies as yet. In addition, the largest and most recent longevity GWAS, based on cases belonging to the top 10% oldest survivors, again only replicated association of the APOE locus 32 .…”

“…In previous work, we showed that longevity defined as top 10% survivors or more extreme is transmitted to subsequent generations 16 . With this, a consistent definition of longevity was provided that is also adopted in the largest longevity GWAS up to now 32 . In addition, we showed that every additional long-lived relative independently contributes to the survival advantage of study participants, according to their genetic distance 16 .…”