Genetic Insights Into the Interplay Between Aging and Kidney Health.

Abstract

The aging process markedly amplifies the risk of kidney diseases, whereas kidney dysfunction also accelerates aging. However, the intricate interplay between aging and kidney diseases remains incompletely understood. In this context, we conducted a comprehensive genetic investigation by incorporating multivariate aging indicators and multiple kidney phenotypes. We explored their shared genetic architecture for each trait pair through cross-trait analyses, and two-step mediation analyses were employed to investigate the mediating role of plasma metabolites in causal relationships. Our findings revealed significant negative correlations between healthy aging and kidney diseases, kidney injury, and kidney function decline. We identified 949 pleiotropic single nucleotide polymorphisms, 85 candidate pleiotropic genes, and 8 shared causal genes across tissues, including SH2B3 and MAP2K1 as druggable genes. Notably, mediation analyses highlighted the crucial role of lipoprotein in mediating the detrimental causal effects of kidney diseases on healthy aging. These findings underscore the complex shared genetic etiology and mediators between aging and kidney phenotypes, offering novel insights into their underlying mechanisms and highlighting potential therapeutic strategies.