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

Abstract

This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people. Five genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by 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 to perform rare variant burden analysis, protein structure, and modelling analysis in-silico. Out of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and of those variants, 22 were considered likely pathogenic 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. Protein modelling demonstrated variants that appeared to likely cause significant structural alterations. This 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.

Figure 1

ABCB4 variant summary in a 2-dimensional illustration. 41 variants are divided into their phenotypic presentation and coloured by: No phenotype previously reported (n = 19), cholestatic phenotype reported in the literature (n = 9), gallstone disease (n = 7), cholangiocarcinoma (n = 1), and intrahepatic cholestasis of pregnancy (n = 5). Bold border represents variants that are unique to the Genes & Health cohort. Topo2 software (Johns S.J., TOPO2, Transmembrane protein display software, http://www.sacs.ucsf.edu/TOPO2) was used for illustration.

Figure 2

ABCB11 variant summary in a 2-dimensional illustration. 48 variants are divided into their phenotypic presentation and coloured by: No phenotype previously reported (n = 19), cholestatic phenotype reported in the literature (n = 14), gallstone disease (n = 10), and intrahepatic cholestasis of pregnancy (n = 5). Bold border represents variants that are unique to the Genes & Health cohort. Topo2 software (Johns S.J., TOPO2, Transmembrane protein display software, http://www.sacs.ucsf.edu/TOPO2) was used for illustration.

Figure 3

ATP8B1 variant summary in a 2-dimensional illustration. 31 variants are divided into their phenotypic presentation and coloured by: No phenotype previously reported (n = 15), cholestatic phenotype reported in the literature (n = 7), gallstone disease (n = 7), liver cirrhosis (n = 1), Liver cirrhosis and multiple cholestatic phenotype (n = 1), and intrahepatic cholestasis of pregnancy (n = 2). Bold border represents variants that are unique to the Genes & Health cohort. Topo2 software (Johns S.J., TOPO2, Transmembrane protein display software, http://www.sacs.ucsf.edu/TOPO2) was used for illustration.