Abstract PR014: Shared germline architecture across renal cell carcinoma, coronary artery disease, and clonal hematopoiesis implicates a regulatory haplotype at the TERT promoter

Abstract Clonal hematopoiesis (CH) has been implicated in both cancer and cardiovascular disease, but a shared germline architecture connecting renal cell carcinoma (RCC), coronary artery disease (CAD), and hematopoietic traits remains unclear. We aimed to map shared germline architecture across RCC, CAD, and hematopoietic traits using an unbiased genome-wide-to-locus workflow, and to prioritize biological pathways for follow-up based on convergent signals. We performed genome-wide genetic correlation (high-definition likelihood, HDL) across RCC, CAD and hematopoietic phenotypes (CH of indeterminate potential [CHIP], loss of Y, loss of X, mosaic chromosomal alterations, and telomere length [TL]), followed by linkage disequilibrium (LD)-aware Bayesian colocalization (coloc and SuSiE-coloc) using harmonized GRCh38/rsID-aligned summary statistics from previously published genome-wide association studies (GWAS). Prompted by robust TERT-promoter colocalization, we conducted secondary, hypothesis-generating, cis-Mendelian randomization (MR) restricted to the TERT promoter window (chr5:1,258,437-1,358,437; 2- and 4-SNP instruments based on shared credible-set variants). Significant genetic correlations were observed for RCC-CAD (rg=0.125, P=1.20×10-4), RCC-TL (rg=0.093, P=1.42×10-2), RCC-CHIP (rg=0.182, P=2.30×10-2), and CAD-TL (rg=-0.173, P=1.03×10-11, false-discovery rate [FDR]