Genetic study of intrahepatic cholestasis of pregnancy in Chinese women unveils East Asian etiology linked to historic HBV epidemic
Abstract
Background & aims: Intrahepatic cholestasis of pregnancy (ICP) is the most common and high-risk liver disorder during pregnancy, with varying prevalence across populations. Our understanding of the mechanisms underlying ICP and its population difference remains limited. This study delves into the genetic etiology of ICP in East Asians, drawing comparisons with Europeans to comprehend ICP etiology in the context of genetic background and evolution. Methods: We conducted the hitherto largest-scale genome-wide association studies (GWAS) on fasting total serum bile acids (TBA) and ICP in 98,269 Chinese pregnancies. The findings were replicated in three cohorts and compared with European populations. Additionally, phenome-wide association and spatio-temporal evolution analyses were employed to investigate the function and evolutionary patterns of ICP-associated loci. Results: We identified eight loci for fasting TBA and four for ICP, including ten novel loci. Notably, we discovered an East-Asian-specific locus within a 0.4Mbp region at 14q24.1, which increases fasting TBA by 6.12 μmol/L and ICP risk by 16.56-fold per risk allele (95% CI: 16.43 to 16.69, P = 7.06×10-381). Phenome-wide association and spatial-temporal evolution analyses revealed that this 14q24.1 ICP risk locus confers resistance to hepatitis B and has become prevalent in East and Southeast Asia within the last 3,000 years. Conclusions: We uncovered a distinct genetic etiology of ICP in East Asians, likely linked to a historic HBV epidemic in East and Southeast Asia within the last 3,000 years. These findings enhance our understanding of ICP pathophysiology and offer potential for more precise detection, assessment, and treatment of the disorder. Impact and implications: This study provides novel insights into the genetic basis of intrahepatic cholestasis of pregnancy (ICP) in East Asian populations, where little was previously known. The identification of the East-Asian-specific 14q24.1 locus, associated with both fasting TBA and ICP, and its connection to a historical hepatitis B epidemic emphasize the importance of incorporating population-specific history into disease research. These findings are crucial for researchers studying pregnancy-related liver disorders and clinicians providing care to pregnant women, enabling more accurate screening, risk assessment, and targeted interventions for ICP.
Yanhong Liu
PhD student
Yuandan Wei
Master student
Yuqin Gu
PhD student
Zijing Yang
Master student
Xinxin Guo
Master student
Hao Zheng
Master student
Siyang Liu
Associate Professor, School of Public Health (Shenzhen), Sun Yat-sen University
Focused on human genomics and bioinformatics research