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

Area of Science:

• Genetics
• Longevity Research
• Human Aging

Background:

• Human longevity is a heritable trait, yet genome-wide association (GWA) studies have yielded limited success in identifying contributing genetic factors.
• Previous research has indicated the involvement of specific genes, but a comprehensive understanding of the genetic architecture of extreme longevity remains incomplete.

Purpose of the Study:

• To conduct meta-analyses of GWA studies using a stringent definition of longevity to identify genetic variants associated with exceptional lifespan.
• To explore gene-level associations and the role of tissue-specific gene expression in human longevity.
• To investigate the genetic correlation between longevity and various disease-related phenotypes.

Main Methods:

• Performed two meta-analyses of GWA studies on a rigorous longevity phenotype.
• Included a large cohort of cases (11,262/3484) surviving to the 90th/99th percentile ages and controls (25,483) with earlier mortality.
• Utilized gene-level association analysis and genetic correlation analyses with disease phenotypes.

Main Results:

• Confirmed the association of rs429358 (apolipoprotein E (ApoE) ε4) with decreased odds of extreme longevity and rs7412 (ApoE ε2) with increased odds.
• Identified a novel association of rs7676745, near GPR78, with reduced odds of surviving to the 90th percentile.
• Gene-level analysis highlighted the importance of tissue-specific gene expression in longevity, and genetic correlation suggested shared genetic architecture between health and longevity.

Conclusions:

• The genetic basis of human longevity is complex, involving known genes like ApoE and novel loci such as GPR78.
• Tissue-specific gene expression patterns are crucial for understanding longevity.
• Longevity shares a significant genetic architecture with various health and disease-related traits, implying that genetic factors influencing disease risk may also impact lifespan.