Seven genetic variants associated with an increased risk of cirrhosis, including p.Cys130Arg missense variant in APOE, among several others, have been newly identified, according to the results of a study published in Gastroenterology.

A multitrait genome-wide association study (GWAS) was conducted that combined cirrhosis rates and alanine aminotransferase (ALT) levels from 5 discovery studies. These studies included the UK Biobank, Vanderbilt BioVU, the Atherosclerosis Risk in Communities study, and 2 case-control studies. Overall, the population consisted of 4829 participants with cirrhosis, 72,705 healthy controls, and 362,539 people with defined ALT levels.

Researchers tested the identified genetic variants associated with cirrhosis at genome-wide significance in independent replication studies, including the Partners HealthCare Biobank, FinnGen, and Biobank Japan. These studies consisted of 3554 patients with cirrhosis and 343,826 healthy controls. Additionally, the investigators tested a polygenic score comprising 12 cirrhosis-associated genetic variants in the Partners HealthCare Biobank.

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The conventional single-trait GWAS for cirrhosis identified 4 variants previously associated with cirrhosis. These variants were near PNPLA3, TM6SF2, HSD17B13, and SERPINA1 (P <5 ´ 10-8 for each). Additionally, a second single-trait GWAS study performed for ALT concentrations identified 19 associated variants, including those near the PNPLA3, TM6SF2, HSD17B13, SERPINA1, and MARC1 gene regions. The effect of a variant on cirrhosis was associated with its impact on circulating ALT levels across the 3.1 million genetic variants in this study (P <.001).

Also, the researchers found 7 newly identified genetic variants associated with cirrhosis in the multitrait GWAS by jointly analyzing levels of ALT and cirrhosis. These variants included rs12904 (odds ratio [OR], 0.90; 95% CI, 0.86-0.95), rs888655 (OR, 0.93; 95% CI, 0.88-0.98), rs9398804 (OR, 0.93; 95% CI, 0.89-0.98), rs7029757 (OR, 0.85; 95% CI, 0.77-0.93), rs1799992 (OR, 1.23; 95% CI, 1.08-1.43), rs429358 (OR, 0.85; 95% CI, 0.79-0.92), and rs1883711 (OR, 1.21; 95% CI, 1.05-1.40).

Overall, the 7 newly identified variants and the 5 known variants (rs2642438, rs6834314, rs28929474, rs58542926, and rs738409) were used to generate the polygenic score. In participants from the Partners HealthCare Biobank, a high polygenic score correlated with a significantly increased risk of cirrhosis compared with the lowest quartile (OR, 2.26; P <.001). Those in the top 1% of distribution and with extreme polygenic risk had an even more pronounced risk of cirrhosis (OR, 3.16; P <.001).

A limitation of this study was the inclusion of cohorts with mostly participants of European descent, which may limit the generalizability of the study’s results.

The researchers concluded that “a polygenic score composed of” the identified 12 genetic variants in this study “may have utility in identifying individuals at high risk of progression to cirrhosis.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Emdin CA, Haas M, Ajmera V, et al. Association of genetic variation with cirrhosis: a multi-trait genome-wide association and gene-environment interaction study. Gastroenterology. Published online December 10, 2020. doi:10.1053/j.gastro.2020.12.011