Major Genetic Risk Factors for Dupuytren's Disease Are Inherited From Neandertals

Abstract

Dupuytren's disease is characterized by fingers becoming permanently bent in a flexed position. Whereas people of African ancestry are rarely afflicted by Dupuytren's disease, up to ∼30% of men over 60 years suffer from this condition in northern Europe. Here, we meta-analyze 3 biobanks comprising 7,871 cases and 645,880 controls and find 61 genome-wide significant variants associated with Dupuytren's disease. We show that 3 of the 61 loci harbor alleles of Neandertal origin, including the second and third most strongly associated ones (P = 6.4 × 10−132 and P = 9.2 × 10−69, respectively). For the most strongly associated Neandertal variant, we identify EPDR1 as the causal gene. Dupuytren's disease is an example of how admixture with Neandertals has shaped regional differences in disease prevalence.

A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren’s disease

“…All 26 previously identified loci from the previous (UK) GWAS 12 were confirmed, but for six loci the effects were found to be heterogeneous between the six cohorts and were therefore excluded from our meta-GWAS (Supplementary Data 4 ). We also found associations with 45 of the 61 loci implicated by Agren et al 13 . Forest plots of the significantly associated SNPs are shown in Supplementary Fig.…”

“…We thus chose not to include these cohorts in our meta-analysis, but rather compare the results. From the 56 regions that we identified, Agren et al also implicated 45, among which 25 that were already reported previously 11 – 13 . The eleven additional loci include the genes MTOR, BABAM2, LRRC3B, LIMD1, LPP, AFAP1, LOC101927691, TFEB, MICAL2, MEOX1 , and ADAMTS5 .…”

“…Very recently, a meta-analysis of DD GWAS was performed using the results from three biobanks (UK Biobank, FinnGen, and Michigan Genomics Initiative) 13 . For this study, the authors identified DD cases based on available International Classification of Diseases codes (ICD, Ninth Revision, Clinical Modification; code 728.71) available from hospital inpatient data.…”

“…Intriguingly, adiposity is causally protective against DD 9 , 10 . Genome-wide associations studies (GWASs) have so far identified 61 genetic risk variants 11 – 13 . The overall (broad-sense) heritability of DD was estimated to be 80%, of which 67% is attributable to common genetic variants 8 , 14 .…”