Genetic links between multimorbidity and human aging.

Abstract

The growing epidemiological burden of multimorbidity among older adults underscores an urgent need to develop interventions that can address multiple age-related diseases (ARDs) at once. Yet, the biological mechanisms driving their co-occurrence remain poorly understood. In this study, we conducted a multivariate genome-wide association analysis to dissect the shared genetic architecture of five common ARDs: heart attack, high cholesterol, hypertension, stroke, and type 2 diabetes. We defined this shared genetic component as the multivariate age-related disease factor (mvARD) and identified 263 independent variants across 180 genomic loci associated with mvARD. These variants were significantly enriched for associations with extreme human longevity, lending empirical support for the geroscience hypothesis in humans. Integrative gene prioritization using transcriptome-wide association studies, colocalization analysis, and Mendelian randomization identified four high-confidence genes in blood-DCAF16, PHF13, MGA, and GTF2B-with putative causal roles on mvARD. Using two-sample Mendelian randomization, we also found several modifiable lifestyle factors, including body mass index and dietary intake, that causally influenced the risk for multiple ARDs. Together, our findings revealed a shared genetic basis for common ARDs that overlapped with the biology of human aging and pointed to potential molecular and behavioral targets for delaying disease onset and promoting healthy aging.