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.

Keywords: Dupuytren's disease; EPDR1; Neandertals; genome-wide association studies; risk variant; splicing quantitative trait loci.

Fig. 1.

Genome-wide associations with Dupuytren's disease in 7,871 cases and 645,880 controls. Meta-analysis of UK Biobank, FinnGen, and MGI. The dotted horizontal line represents the genome-wide significance threshold (P = 5 × 10⁻⁸). Coordinates are in hg38. See supplementary table S1, Supplementary Material online for genome-wide significant loci.

Fig. 2.

Archaic haplotypes in present-day carriers of 3 Dupuytren's disease risk variants. Three Neandertal genomes (Vindija, Chagyrskaya, and Altai) and 1 Denisova genome were used as archaic references (Meyer et al. 2012, Prüfer et al. 2014, 2017, Mafessoni et al. 2020). Archaic haplotype lengths were calculated using identity by descent (Chen et al. 2020). (A–C) Haplotype lengths and counts associated with (A) the second major risk allele (chr7:37,984,972G/A, hg38), (B) the third major risk allele (chr8:69,142,848G/A, hg38), and (C) the chr17 risk allele (chr17:13,547,115C/T, hg38). See table 1 for risk associations and haplotype counts.

Fig. 3.

Fine-mapping of the Neandertal haplotype. (A) Z-score for association with Dupuytren's disease (Z_{Dupuytren's disease}) as a function of linkage disequilibrium (r) with the most significant risk variant on chromosome 7 (rs17171240, chr7:37,984,972G/A, hg38; marked in red). Variants marked in green are in full linkage disequilibrium (r² = 1.00) with rs17171240. Linkage disequilibrium data are from the 1000 Genomes Project (Auton et al. 2015). (B) P values for Dupuytren's disease associations (upper panel) and posterior inclusion probabilities (PIP; lower panel) for causal variants derived from fine-mapping under the assumption of one causal variant (Pruim et al. 2010, Boughton et al. 2021).

Fig. 4.

The Neandertal haplotype is associated with alternative splicing of EPDR1. (A) Genotype-tissue expression project-derived cis-splicing quantitative trait loci for the Neandertal haplotype lead variant (Lonsdale et al. 2013). rs17171240 (chr7:37,984,972G/A, hg38) reduces the intron excision ratio of the EPDR1 transcript in skeletal muscle (normalized effect size [NES] = −0.77, P = 1.7 × 10⁻²³, GG, n = 581, GA, n = 118, AA = 7; left panel), adipose tissue (NES = −0.63, P = 1.1 × 10⁻¹¹, GG, n = 481, GA, n = 93, AA = 7; middle panel), and cultured fibroblasts (NES = −0.60, P = 5.9 × 10⁻⁸, GG, n = 393, GA, n = 84, AA = 6; right panel). (B) The long EPDR1 isoform (NM_017549.5) consists of exons 1–3, translating into the 290 amino acid ependymin related protein 1 (EPDR1). The short EPDR1 isoform (NM_001242946.2) is produced by alternative splicing at base pair 570, creating an out-of-frame stop codon (TGA) that translates into a truncated protein of 90 amino acids. (C) X-ray crystallography-derived structure of EPDR1 (PDB: 6E7O; Wei et al. 2019) in dimeric form from 2 angles. Amino acids 37/38 to 222, respectively, are shown. (D) Structure of the truncated EPDR1 (amino acids 37/38 to 90) from 2 angles. The lipid binding pocket and dimerization interface are disrupted.

Fig. 5.

Genetic architecture of the chromosome 7 risk region. Association strengths with Dupuytren's disease for the risk region located on chromosome 7. Notably, there are 3 independent haplotypes (blue, yellow, and red horizontal lines) associated with Dupuytren's disease, separated by recombination hotspots. In each window, the variants in high LD (r² > 0.8) are colored in red (rs17171240, chr7:37,984,972G/A, hg38; index for Neandertal haplotype), yellow (rs2598104, chr7:37,937,647 T/C, hg38), and blue (rs6462793, chr7:37,887,948G/C, hg38), respectively. Recombination rates are derived from the 1000 Genomes Project (Auton et al. 2015).