Polygenic effects of common single-nucleotide polymorphisms on life span: when association meets causality

Area of Science:

• Genetics
• Longevity Research
• Biostatistics

Background:

• Human lifespan is influenced by numerous common single-nucleotide polymorphisms (SNPs), each with a minor individual impact.
• Previous research indicated a polygenic contribution to longevity.

Purpose of the Study:

• To further investigate the polygenic influence on human lifespan.
• To identify specific SNPs associated with longevity and explore their biological mechanisms.

Main Methods:

• Utilized Framingham Heart Study 550K SNP data.
• Employed six distinct statistical procedures (linear regression, Cox regression, logistic regression, generalized estimation equation, mixed model, gene frequency method) to identify prolongevity SNP alleles.
• Reviewed literature on the functions of genes nearest to the identified SNPs.

Main Results:

• Identified six sets of prolongevity SNP alleles, with significant additive influence on lifespan found in each set.
• A core set of 27 SNPs consistently influenced lifespan across all statistical procedures.
• A higher proportion (74%) of these core SNPs were located within genes compared to the overall dataset (40%).
• Genes associated with the identified SNPs are predominantly involved in aging, cancer, and brain disorders.

Conclusions:

• Polygenic effects significantly contribute to the genetic influence on human lifespan.
• A consistent core set of longevity-associated SNPs exists, regardless of the statistical method used for selection.
• The functional relevance of associated genes to aging and major diseases supports a causal link between these SNPs and lifespan, indicating high confidence in true positive associations.