A Genetic Risk Variant Associated With the Risk of Primary Biliary Cholangitis Is Inherited From Neanderthals
Alessio Gerussi, Chiara Caime, Harold Wang, Heather J. Cordell, George F. Mells, Richard N. Sandford, David E. Jones, Gideon Hirschfield, Katherine A. Siminovitch, M. Eric Gershwin, Brian D. Juran, Elizabeth J. Atkinson, Angela Cheung, Mariza de Andrade, Aris Baras, Konstantinos N. Lazaridis, Rosanna Asselta, Pietro Invernizzi, Manuela Sironi, Sriram Sankararaman, , ,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.