Author:
Zöllner Julia,Finer Sarah,Linton Kenneth J.,Akhtar Shaheen,Anwar Mohammad,Arciero Elena,Ashraf Samina,Bidi Saeed,Breen Gerome,Broster James,Chung Raymond,Collier David,Curtis Charles J.,Chaudhary Shabana,Clinch Megan,Colligan Grainne,Deloukas Panos,Durham Ceri,Durrani Faiza,Eto Fabiola,Finer Sarah,Gafton Joseph,Garcia Ana Angel,Griffiths Chris,Harvey Joanne,Heng Teng,Hodgson Sam,Huang Qin Qin,Hurles Matt,Hunt Karen A.,Hussain Shapna,Islam Kamrul,Iyer Vivek,Jacobs Ben,Khan Ahsan,Lavery Cath,Lee Sang Hyuck,Lerner Robin,MacArthur Daniel,Malawsky Daniel,Martin Hilary,Mason Dan,Mathur Rohini,Mazid Mohammed Bodrul,McDermott John,Morton Caroline,Newman Bill,Owor Elizabeth,Qureshi Asma,Rahman Samiha,Ramachandrappa Shwetha,Reza Mehru,Russell Jessry,Safa Nishat,Samuel Miriam,Simpson Michael,Solly John,Spreckley Marie,Stow Daniel,Taylor Michael,Trembath Richard C.,Tricker Karen,Uddin Nasir,van Heel David A.,Walter Klaudia,Winckley Caroline,Wood Suzanne,Wright John,Zöllner Julia,van Heel David A.,Williamson Catherine,Dixon Peter H.,
Abstract
AbstractThis 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.
Funder
National Institute for Health and Care Research
Publisher
Springer Science and Business Media LLC