Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom

ObjectivesThis study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people in the United Kingdom as they are an understudied genetic ancestry group with disproportionate disease burden. MethodsFive genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by low/mid whole exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency <5%. Variants were filtered and annotated. Rare variant burden analysis was conducted. Variants associated with a phenotype or predicted to be likely pathogenic (LP) underwent protein structure and modelling analysis in silico. ResultsOut of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and unique to this cohort and not previously reported in the GnomAD database. Of those novel variants, 22 were considered LP and 9 pathogenic. We identified variants in volunteers with gallstone disease (n=31), intrahepatic cholestasis of pregnancy (ICP, n=16), cholangiocarcinoma and cirrhosis (n=2). Fourteen novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. The rare variant burden was significantly increased in ABCB11. A total of 73 variants were assessed for impact at the protein level. Protein modelling demonstrated variants that appeared to likely cause significant structural damage. ConclusionsThis study highlights the significant genetic burden contributing to cholestatic liver disease. Novel likely pathogenic and pathogenic variants were identified addressing the underrepresentation of diverse ancestry groups in genomic research. WHAT IS KNOWNCholestatic liver diseases encompass a broad range of conditions. Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disease. Genetic and environmental factors contribute to the aetiology of cholestatic disease. South Asian populations are disproportionally affected. WHAT IS NEW HEREExome sequencing analysis in a British Pakistani and Bangladeshi population discovered new genetic mutations. Pathogenic variants were identified that increase risk of cholestatic liver disease. Novel variants that contribute to ICP were identified.