NEW YORK – An international team led by investigators at the Karolinska Institute has traced genetic contributors to a fibroproliferative hand condition called Dupuytren's disease back to introgressed sequences introduced into the human genome via mixing with Neanderthals.
Dupuytren's disease, nicknamed "Viking disease" due to its prevalence in northern Europe, is marked by constricted hand movements that eventually cause hands to freeze in a flexed position. The condition is particularly common in individuals of northern European ancestry, though it has also been linked to risk factors ranging from age or a diabetes diagnosis to alcohol consumption.
"Whereas people of African ancestry are rarely afflicted by Dupuytren's disease, up to [about 30 percent] of men over 60 years [old] suffer from this condition in northern Europe," senior and corresponding author Hugo Zeberg, a physiology and pharmacology researcher with the Karolinska Institute, the Max Planck Institute for Evolutionary Anthropology, and the Okinawa Institute of Science and Technology's Human Evolutionary Genomics Unit, and his colleagues wrote in their study, published Wednesday in Molecular Biology and Evolution.
To build on the 36 genetic variants associated with Dupuytren's disease in the past, the team did genome-wide analyses and a meta-analysis involving individuals with or without the hand condition from three cohorts: the UK Biobank Project, FinnGen, and the Michigan Genomics Initiative.
Consistent with past studies, the condition was more common in participants of European ancestry than in individuals of African descent, turning up in nearly 1.4 percent of the European ancestry individuals considered, but just 0.49 percent of individuals of African ancestry.
With genetic data for 7,871 Dupuytren's disease-affected individuals and 645,880 unaffected control individuals, the investigators narrowed in on 61 Dupuytren's disease-associated variants, including 21 risk variants not reported previously.
While many of these genetic risk factors had been identified in the past, the Dupuytren's disease-related variants originating in Neanderthal-introgressed sequences had not, Zeberg explained in an email.
With a series of follow-up fine-mapping, linkage disequilibrium, quantitative trait locus, Mendelian randomization, and other analyses, the researchers identified and started characterizing three new Dupuytren's disease risk variants in Neanderthal introgressed sequences.
The most pronounced Neanderthal-related association involved a chromosome 7 variant that appeared to influence transcript splicing for a gene called EPDR1 in muscle and adipose tissues and in culture fibroblast cells, the researchers reported.
"[W]e were able to identify the causal gene of one of the genetic risk factors," Zeberg explained.
While a specific Dupuytren's disease-related role for the protein encoded by EPDR1 is yet to be determined, he explained, the current analysis highlighted a causal role for the gene, potentially pointing to an avenue for future treatment options.
"This is a case where the meeting with Neanderthals has affected who suffers from illness," Zeberg said in a statement. Nevertheless, he noted that "we should not exaggerate the connection between Neanderthals and [Viking's disease]" since the risk factors passed down from the archaic hominin represent a small proportion of the overall genetic risk identified.