Byun Jinyoung, Kim Hyun-Seok, Han Younghun, Thrift Aaron P, Lin Sabrina M, Xiao Xiangjun, Lim Hyeyeun, Jun Goo, Desantis Stacia M, El-Serag Hashem B, Kanwal Fasiha, Amos Christopher I
Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas, USA.
Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
Liver Int Commun. 2024 Dec;5(4). doi: 10.1002/lci2.70002. Epub 2024 Nov 15.
BACKGROUND & AIMS: Cirrhosis is a leading cause of liver-related mortality and a multifactorial disease. To date, the complex genetic architecture of non-viral cirrhosis has not been fully explored. Cross-trait genetic correlations can elucidate the common genetic etiology of genetically correlated phenotypes. This study aims to identify polygenic and pleiotropic traits associated with cirrhosis using the linkage disequilibrium score regression analysis.
We conducted genome-wide association analysis of 9,622,842 imputed SNPs on 3,368 non-viral cirrhosis cases and 258,258 controls, and cross-trait analysis between non-viral cirrhosis and various polygenic and pleiotropic traits using the UK Biobank cohort study. We further performed sensitivity analyses by removing genomic regions of alcohol intake, smoking behaviors, and obesity. We observed multiple traits showing robust genetic correlations (rg) with non-viral cirrhosis.
We found strong genetic correlations between the genetic architectures of non-viral cirrhosis and clinical/physiologic factors, including BMI (rg=0.82), alanine aminotransferase (0.71), diabetes (0.70), number of cigarettes currently smoked daily (0.67), amount of alcohol drunk on a typical drinking day (0.60), insomnia (0.59), gout (0.57), depression (0.50), apoliprotein-A (-0.33), HDL cholesterol (-0.49). Exclusion of genomic regions associated with alcohol intake, smoking behaviors, and obesity demonstrated consistent directions and persistent associations in genetic patterns. The inheritability of cirrhosis on the observed scale showed 0.56%.
This study provides a comprehensive assessment of the shared genetic architecture of non-viral cirrhosis predisposition and numerous polygenic and pleiotropic traits, most notably BMI, alanine aminotransferase, and diabetes. These findings provide new information on underlying comorbid conditions that can increase the non-viral cirrhosis risk.
肝硬化是肝脏相关死亡的主要原因，是一种多因素疾病。迄今为止，非病毒性肝硬化复杂的遗传结构尚未得到充分探索。跨性状遗传相关性能够阐明遗传相关表型的共同遗传病因。本研究旨在使用连锁不平衡评分回归分析来识别与肝硬化相关的多基因和多效性性状。
我们对3368例非病毒性肝硬化病例和258258例对照的9622842个推测单核苷酸多态性（SNP）进行了全基因组关联分析，并利用英国生物银行队列研究对非病毒性肝硬化与各种多基因和多效性性状进行了跨性状分析。我们通过去除酒精摄入量、吸烟行为和肥胖的基因组区域进一步进行了敏感性分析。我们观察到多个性状与非病毒性肝硬化表现出强烈的遗传相关性（rg）。
我们发现非病毒性肝硬化的遗传结构与临床/生理因素之间存在很强的遗传相关性，包括体重指数（rg = 0.82）、丙氨酸转氨酶（0.71）、糖尿病（0.70）、当前每日吸烟量（0.67）、典型饮酒日饮酒量（0.60）、失眠（0.59）、痛风（0.57）、抑郁症（0.50）、载脂蛋白A（-0.33）、高密度脂蛋白胆固醇（-0.49）。排除与酒精摄入量、吸烟行为和肥胖相关的基因组区域后，遗传模式呈现出一致的方向和持续的关联。观察范围内肝硬化的遗传率为0.56%。
本研究对非病毒性肝硬化易感性与众多多基因和多效性性状，尤其是体重指数、丙氨酸转氨酶和糖尿病之间共享的遗传结构进行了全面评估。这些发现为可能增加非病毒性肝硬化风险的潜在合并症提供了新信息。
