How genetic risk contributes to autoimmune liver disease

Semin Immunopathol. 2022 Jul;44(4):397-410. doi: 10.1007/s00281-022-00950-8. Epub 2022 Jun 1.


Genome-wide association studies (GWAS) for autoimmune hepatitis (AIH) and GWAS/genome-wide meta-analyses (GWMA) for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) have been successful over the past decade, identifying about 100 susceptibility loci in the human genome, with strong associations with the HLA locus and many susceptibility variants outside the HLA locus with relatively low risk. However, identifying causative variants and genes and determining their effects on liver cells and their immunological microenvironment is far from trivial. Polygenic risk scores (PRSs) based on current genome-wide data have limited potential to predict individual disease risk. Interestingly, results of mediated expression score regression analysis provide evidence that a substantial portion of gene expression at susceptibility loci is mediated by genetic risk variants, in contrast to many other complex diseases. Genome- and transcriptome-wide comparisons between AIH, PBC, and PSC could help to better delineate the shared inherited component of autoimmune liver diseases (AILDs), and statistical fine-mapping, chromosome X-wide association testing, and genome-wide in silico drug screening approaches recently applied to GWMA data from PBC could potentially be successfully applied to AIH and PSC. Initial successes through single-cell RNA sequencing (scRNA-seq) experiments in PBC and PSC now raise high hopes for understanding the impact of genetic risk variants in the context of liver-resident immune cells and liver cell subpopulations, and for bridging the gap between genetics and disease.

Keywords: Autoimmune hepatitis; Genome-wide association studies (GWAS); Genome-wide meta-analyses (GWMA); HLA; Mediated expression score regression; Non-HLA; Polygenic risk score; Primary biliary cholangitis; Primary sclerosing cholangitis.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmune Diseases* / genetics
  • Cholangitis, Sclerosing* / genetics
  • Genome-Wide Association Study
  • Hepatitis, Autoimmune* / genetics
  • Humans
  • Liver Cirrhosis, Biliary* / etiology
  • Liver Cirrhosis, Biliary* / genetics
  • Liver Diseases*
  • Risk Factors