# Linkage disequilibrium score regression identifies genetic correlations between hepatocellular carcinoma and clinically relevant traits

## TL;DR

This study uses genetic data to find links between nonviral liver cancer and traits like diabetes and high blood pressure, suggesting shared genetic factors.

## Contribution

The study identifies novel genetic correlations between nonviral hepatocellular carcinoma and metabolic and liver-related traits using linkage disequilibrium score regression.

## Key findings

- Positive genetic correlations were found between nonviral HCC and blood biomarkers of liver injury and allostatic load.
- Genetic links were observed between nonviral HCC and diseases like diabetes, hypertension, and heart disease.
- The findings suggest shared genetic pathways between nonviral HCC and metabolic dysfunction-associated liver disease.

## Abstract

Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Hepatocellular carcinoma arises from a combination of environmental and genetic factors, with the latter playing a potentially more significant role in nonviral hepatocellular carcinoma. Here, the authors characterized the genetic correlations and heritability between nonviral hepatocellular carcinoma and 901 epidemiologic, behavioral, and clinical traits derived from the United Kingdom Biobank using linkage disequilibrium score regression. They found positive genetic correlations between nonviral hepatocellular carcinoma and blood‐based liver injury and allostatic load biomarkers as well as other diseases including diabetes, hypertension, and chronic ischemic heart disease. The findings offer an atlas of genetic associations for further investigation into hepatocellular carcinoma etiology.