Language

English

Publication Date

10-1-2026

Journal

Liver International

DOI

10.1111/liv.70868

PMID

42773620

PMCID

PMC13598353

PubMedCentral® Posted Date

9-22-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Primary Biliary Cholangitis (PBC) is an autoimmune cholangiopathy with polygenic architecture and unknown aetiology. Evidence links Neanderthal-derived genetic variants to autoimmune conditions; however, their contribution to PBC susceptibility remains unexplored.

Objective: We investigate whether archaic alleles influence PBC risk.

Design: Genotype data from four PBC cohorts were analysed: CANUK (4615 cases, 9233 controls), OLD IT (444 cases, 901 controls), NEW IT (255 cases, 579 controls) and MAYO (891 cases, 621 controls). Association testing with 235 592 Neanderthal Informative Markers (NIMs) was performed, adjusting for population stratification. Heritability was estimated using RHE-mc and temporal haplotype dynamics were assessed using ancient DNA data from Europe and Asia.

Results: A Neanderthal-derived variant in TNPO3 (rs12531711), previously reported by Cordell et al. showed strong association in CANUK (p = 2.04 × 10-26) and replicated across all validation cohorts. This variant functions as an eQTL, upregulating IRF5 and downregulating TNPO3 in blood. It is rare in African populations but common both in Europeans and Asians. Temporal analysis of the haplotype carrying rs12531711 revealed frequency increased substantially during the Bronze Age (5000-3000 BP), rising from 2.0% to 7.7% in Europe and 3.4% to 17.4% in Asia, before stabilizing. Despite this strong single-variant association, the heritability explained by NIMs was not significantly different from that of non-NIM variants.

Conclusion: A Neanderthal-derived variant contributes to PBC risk and its frequency increased in the Bronze Age, possibly due to pathogen-driven selection. Archaic introgression overall has limited influence on PBC heritability. Functional studies are needed to elucidate the role of rs12531711.

Keywords

Female, Humans, Male, Case-Control Studies, Europe, European People, Genetic Predisposition to Disease, Haplotypes, Interferon Regulatory Factors, Liver Cirrhosis, Biliary, Neanderthals, Polymorphism, Single Nucleotide, Asian People

Published Open-Access

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