Poster #57 - Ananya Rajagopalan

Elucidating the shared genetic architecture of hypercholesterolemia and endometriosis through a mediation framework

Ananya Rajagopalan1 BS, Lindsay Guare1 BS, Aude Ikuzwe1 BS, Lanna Caruth1 BS, Craig Teerlink2 PhD, Danielle Candelieri2 ScD, MPH, Penn Medicine BioBank, Regeneron Genetics Center, Marijana Vujković 3 PhD, Julie Lynch4 RN, PhD, MBA, Shefali Setia-Verma1 PhD 1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Philadelphia, PA, United States 2Departments Primary - Internal Medicine, Adjunct - Family & Preventive Medicine, University of Utah, UT, United States 3Division of Translational Medicine and Human Genetics, Perelman School of Medicine, Philadelphia, PA, United States 4VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System (VINCI), Salt Lake City, UT, USA

Hypercholesterolemia is a complex cardiovascular disorder shaped by genetic, environmental, and lifestyle factors. Individuals with endometriosis are at 1.25-fold increased risk of hypercholesterolemia, with previous work indicating significant genetic correlation between the two conditions. Current genome-wide association studies (GWAS) often overlook underlying mediating pathways, treating SNP effects on hypercholesterolemia as purely direct. We hypothesize that accounting for endometriosis as a potential confounder among women would improve detection of relevant genetic associations with hypercholesterolemia, by mitigating bias from hormone-related metabolic differences. We developed and applied a mediated GWAS methodology that distinguishes between direct genetic effects on hypercholesterolemia and indirect effects from endometriosis. We conducted multi-ancestry, endometriosis-mediated hypercholesterolemia GWAS in 369,832 individuals across four biobanks (AoU, PMBB, MVP, and eMERGE) and six genetically-inferred ancestry groups (EUR, AFR, AMR, EAS, SAS, and MID). We identified 34 genome-wide significant loci, 20 of which are unreported in a previous hypercholesterolemia GWAS. Among the most significant were loci within *GCKR* and *HNF1A*. While not reported in prior hypercholesterolemia GWAS, they are captured in GWAS of lipid traits and metabolic regulation. *GCKR* regulates glucose metabolism levels in liver and pancreatic islet cells and is implicated in previous GWAS for insulin and lipid levels. *HNF1A* encodes a liver-specific transcription factor and is associated with maturity-onset diabetes of the young. Furthermore, 5 of the 34 loci are unreported in prior GWAS of lipid panel measurements and hypercholesterolemia: *LINC01899, LOC102546299, DENND1A, LOC105372096, and RNA5SP189/LOC345571*. Notably, *DENND1A* is associated with polycystic ovary syndrome and shows evidence of regulatory variation (eQTLs) in ovarian tissue, while *LOC102546299* is linked to female CAD survival. *LINC01899* and *RNA5SP189/LOC345571* are associated with smoking initiation, a risk factor for elevated cholesterol. These findings broaden our understanding of the genetic architecture of hypercholesterolemia, highlight potential sex-specific regulatory mechanisms, and point to previously unreported loci for future functional investigation.