Shared genetic architecture between constipation and aging-related phenotypes: Insights from large-scale genome-wide...

While the frequency of constipation increases sharply with age, the genetic links between constipation and aging-related phenotypes remain largely unexplored. So far, research has typically focused only on individual characteristics while neglecting broader genetic connections. In this study, we evaluated the shared genetic architecture of constipation and aging-related phenotypes in order to better understand the causes of aging-related intestinal dysfunction. Using publicly available genome-wide association study summary statistics, we developed a multi-stage analysis pipeline to identify common signals at the variation and genetic levels. We studied 4 aging-related phenotypes: frailty index (FI), telomere length, facial aging and GrimAge acceleration. Our approach combines linkage disequilibrium score regression and high-definition likelihood with Pleiotropy Analysis under Composite Null Hypothesis, functional mapping and annotation and Bayesian colocalization to identify pleiotropic loci, followed by tissue-specific mapping via Multi-marker Analysis of GenoMic Annotation and stratified linkage disequilibrium score regression. Constipation showed a moderate positive genetic correlation with FI in both linkage disequilibrium score regression and high-definition likelihood. The inverse correlation with TL was weak and method-dependent. No significant genome-wide genetic correlation was detected with facial aging or GrimAge acceleration. Multi-layer locus mapping and gene-based analyses prioritized several candidate genes, including MSL2, STAG1, and SRSF9, through different combinations of association-based evidence. However, no gene showed multiple-testing-corrected summary-data-based Mendelian randomization evidence shared between constipation and any of the 4 aging-related phenotypes. Multi-marker Analysis of GenoMic Annotation suggested cerebellar enrichment for genes associated with the constipation-FI pair, whereas stratified linkage disequilibrium score regression identified broader central nervous system enrichment for FI but no significant cell-type enrichment for constipation. These findings support a shared genetic component between constipation and selected aging-related phenotypes and provide candidate loci, genes and tissues for further functional investigation.