Genetic study of intrahepatic cholestasis of pregnancy in 101,023 Chinese women unveils East Asian-specific etiology linked to historic HBV infection

Background & AimsIntrahepatic cholestasis of pregnancy (ICP) is the most common and high-risk liver disorder during the critical period of human reproduction. Despite varying prevalence across populations, a mechanistic understanding of this phenomenon is lacking. 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. MethodsWe conducted the hitherto largest-scale genome-wide association studies (GWAS) on total bile acid concentration (TBA) and ICP among 101,023 Chinese pregnancies. The findings were subsequently replicated in two cohorts and compared with European populations. Additionally, phenome-wide association and spatio-temporal evolution analyses were employed to understand the function and explore evolutionary pattern of sites associated with ICP. ResultsWe identified eight TBA and five ICP loci, including ten novel loci. Notably, we found an East-Asian-specific genetic locus at 14q24.1, contributing to a 6.41 {micro}mol/L increase in TBA and a 15.23-fold higher risk of ICP per risk allele (95% CI: 15.10 to 15.36, P = 9.23x10-375). Phenome-wide association studies and spatial-temporal evolution analyses revealed that the 14q24.1 ICP risk locus exhibits resistance to hepatitis B infection and has become prevalent only within the last 3,000 years in East and Southeast Asia. ConclusionsOur investigations have unraveled a distinct etiology of ICP between Europeans and East Asians, and has linked ICP etiology in East Asians to a historical HBV epidemic in East and Southeast Asia within the last 3,000 years. These findings lay the groundwork for an improved biological understanding of ICP pathophysiology. Further exploration and utilization of these variations hold the potential for more precise detection, assessment, and treatment of ICP. Lay summaryIntrahepatic cholestasis of pregnancy (ICP) is a prevalent and high-risk liver disorder that occurs during pregnancy, a critical period in human reproduction. It affects approximately 1% to 6.06% pregnancies and has been associated with severe adverse outcomes such as preterm birth and stillbirth. While rare and common variants associated with ICP have been identified in the European population, the genetic basis of ICP in East Asian population remains uncharacterized. Here, we conducted the largest-scale genome-wide association studies to date for TBA and ICP among 101,023 Chinese pregnant women, including 4,703 cases and 96,320 controls from two hospitals in Shenzhen, China. We replicated our findings in two independent Chinese cohorts and compared them with ICP genetic studies in the European population. We identified eight and five genome-wide significant loci for TBA and ICP, respectively, including ten novel loci. Notably, we identified an East-Asian-specific genetic locus contributing to a 6.41 {micro}mol/L increase in TBA per risk allele and a 15.23-fold higher risk of ICP. Further exploration through phenome-wide association studies and spatial-temporal evolution analyses revealed that the 14q24.1 ICP risk locus exhibits resistance to hepatitis B infection and has become prevalent only within the last 3,000 years in East and Southeast Asia. These findings suggest a historical HBV epidemic in East and Southeast Asia within 3,000 years may have contributed to the increased prevalence of ICP and TBA risk alleles among East Asians. Our study unravels a distinct genetic etiology of ICP between Europeans and East Asians. These findings lay the foundation for an improved understanding of ICP pathophysiology and emphasize the need for integrating population evolution into genetic medicine for personalized genomics and clinical guidance. Highlights(1) In the most powerful genome-wide association studies on TBA and ICP in East Asians to date, we identified eight and five genetic loci, respectively, of which, 7 and 3 were novel discoveries. (2) One of the novel loci, the 14q24.1 locus, stands out as it contains unique causal genetic variants specific to East-Asians. These variants demonstrate large effects, contributing to an average increase of 6.41 {micro}mol/L in TBA per risk allele and a 15.23-fold higher risk of ICP. (3) The risk mutations associated with ICP at the 14q24.1 exhibit resistance to hepatitis B infection and has only become prevalent within the last 3000 years in East and Southeast Asia. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/24309754v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1e56492org.highwire.dtl.DTLVardef@12dbc93org.highwire.dtl.DTLVardef@1b7774corg.highwire.dtl.DTLVardef@1f94984_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOAbstract Figure:C_FLOATNO Genetic basis and evolutionary history of intrahepatic cholestasis of pregnancy in East Asia. TBA: Total bile Acid. ICP: Pregnancy intrahepatic cholestasis. Refer to the main text for the illustration. C_FIG