Identifying Susceptibility Genes and Shared Genetic Architecture for Longevity and Muscle Weakness.

APOC1 and TOMM40 were consistently identified as longevity-associated genes across multiple TWAS approaches and validated by MAGMA.

• Both genes were identified using multi-tissue and single-tissue TWAS integrated with GTEx v8 eQTL data.
• Longevity GWAS included age >90th percentile (n = 11,262 cases) and age >99th percentile (n = 3,484 cases) cohorts.
• Gene-trait associations were validated using MAGMA as a complementary approach.
• Results were consistent across both longevity definitions (90th and 99th percentile survival).

DYM and TGFA were identified as susceptibility genes for muscle weakness across TWAS approaches and validated by MAGMA.

• Muscle weakness GWAS used two definitions: EWGSOP criteria (n = 48,596 cases) and FNIH criteria (n = 20,335 cases).
• Both genes were identified consistently across multi-tissue and single-tissue TWAS methods.
• Results were validated using MAGMA gene-based analysis.
• Both genes were significant under both EWGSOP and FNIH muscle weakness definitions.

Mendelian randomization analysis showed that higher expression of APOC1 and TOMM40 increased the odds of longevity.

• Both APOC1 and TOMM40 showed OR > 1, p < 0.05 for longevity (age >90th percentile survival).
• MR was applied to test causality between genetically predicted gene expression and longevity.
• These findings suggest a causal role of APOC1 and TOMM40 expression in promoting longevity.

Mendelian randomization analysis showed that higher expression of DYM and TGFA reduced the risk of muscle weakness.

• Both DYM and TGFA showed OR < 1, p < 0.05 for muscle weakness.
• MR analysis tested causal effects of genetically predicted gene expression on muscle weakness risk.
• Results were consistent across both EWGSOP and FNIH muscle weakness definitions.

Colocalization analysis supported shared causal variants for APOC1 and TOMM40 with longevity, with rs429358 as the shared variant.

• APOC1 colocalization posterior probability for shared causal variant (PP.H4) = 0.81.
• TOMM40 colocalization PP.H4 = 0.85.
• The shared variant identified was rs429358 for both genes.
• Colocalization was demonstrated for longevity defined as age >90th survival percentile.

Colocalization analysis supported shared causal variants for DYM and TGFA with muscle weakness under both EWGSOP and FNIH definitions.

• Both DYM and TGFA showed PP.H4 > 0.80 for colocalization with muscle weakness.
• Colocalization was demonstrated under both EWGSOP (n = 48,596) and FNIH (n = 20,335) muscle weakness definitions.
• PP.H4 > 0.80 indicates strong evidence for a shared causal variant between gene expression and muscle weakness GWAS signals.

A significant negative genetic correlation was observed between longevity and muscle weakness.

• Genetic correlation Rg < 0, p < 0.05 between longevity and muscle weakness traits.
• Cross-trait genetic correlation was estimated using linkage disequilibrium score regression (LDSC).
• The negative correlation indicates that genetic factors promoting longevity tend to be inversely associated with genetic factors promoting muscle weakness.

Cross-trait pleiotropy analysis identified several pleiotropic genes and gene clusters influencing both longevity and muscle weakness.

• Pleiotropic genes identified included PVRL2, PPP1R9A, SLC39A8, and the TOMM40/APOE/APOC1 gene cluster.
• Pleiotropy analysis used the PLACO (pleiotropy analysis under the composite null hypothesis) method.
• Pleiotropic loci were annotated using FUMA and MAGMA.
• These loci represent shared genetic architecture linking aging and muscle decline.

The study integrated the largest available GWAS datasets for longevity and muscle weakness with GTEx v8 multi-tissue eQTL data.

• Longevity GWAS: age >90th percentile (n = 11,262 cases) and age >99th percentile (n = 3,484 cases).
• Muscle weakness GWAS: EWGSOP definition (n = 48,596 cases) and FNIH definition (n = 20,335 cases).
• GTEx v8 multi-tissue eQTL data was used for TWAS integration.
• Analytical pipeline included multi-tissue TWAS, single-tissue TWAS, MAGMA, MR, colocalization, LDSC, PLACO, and FUMA annotation.