Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score.

Longevity is a complex phenotype influenced by both environmental and genetic factors. The genetic contribution is estimated at about 25%. Despite extensive research efforts, only a few longevity genes have been validated across populations. Long-lived individuals (LLI) reach extreme ages with a relative low prevalence of chronic disability and major age-related diseases (ARDs). We tested whether the protection from ARDs in LLI can partly be attributed to genetic factors by calculating polygenic risk scores (PRSs) for seven common late-life diseases (Alzheimer's disease (AD), atrial fibrillation (AF), coronary artery disease (CAD), colorectal cancer (CRC), ischemic stroke (ISS), Parkinson's disease (PD) and type 2 diabetes (T2D)). The examined sample comprised 1351 German LLI (≥94 years, including 643 centenarians) and 4680 German younger controls. For all ARD-PRSs tested, the LLI had significantly lower scores than the younger control individuals (areas under the curve (AUCs): ISS = 0.59, p = 2.84 × 10 ^-35 ; AD = 0.59, p = 3.16 × 10 ^-25 ; AF = 0.57, p = 1.07 × 10 ^-16 ; CAD = 0.56, p = 1.88 × 10 ^-12 ; CRC = 0.52, p = 5.85 × 10 ^-3 ; PD = 0.52, p = 1.91 × 10 ^-3 ; T2D = 0.51, p = 2.61 × 10 ^-3 ). We combined the individual ARD-PRSs into a meta-PRS (AUC = 0.64, p = 6.45 × 10 ^-15 ). We also generated two genome-wide polygenic scores for longevity, one with and one without the TOMM40 / APOE / APOC1 gene region (AUC (incl. TOMM40 / APOE / APOC1 ) = 0.56, p = 1.45 × 10 ^-5 , seven variants; AUC (excl. TOMM40 / APOE / APOC1 ) = 0.55, p = 9.85 × 10 ^-3 , 10,361 variants). Furthermore, the inclusion of nine markers from the excluded region (not in LD with each other) plus the APOE haplotype into the model raised the AUC from 0.55 to 0.61. Thus, our results highlight the importance of TOMM40 / APOE / APOC1 as a longevity hub.