Dupuytren's Disease Inherited From Neandertals

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Dupuytren's Disease Inherited From Neandertals Jun 15, 2023 21:59:43 GMT

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Post by Admin on Jun 15, 2023 21:59:43 GMT

Many men in northern Europe over the age of 60 suffer from the so-called Viking disease, which means that the fingers lock in a bent position. Now researchers at Karolinska Institutet, together with colleagues, have used data from over 7,000 affected individuals to look for genetic risk factors for the disease. The findings, which have been published in Molecular Biology and Evolution, show that three of the strongest risk factors are inherited from Neanderthals.

Up to 30 percent of men in northern Europe over 60 suffer from a condition called Dupuytren's contracture. The condition is sometimes called the Viking disease because it mainly affects individuals with northern European ancestry. The disease is significantly more common in men than women and usually begins as a lump in the palm of the hand that grows and causes one or more fingers to lock in a bent position. The condition is usually not painful, but the nodules may sometimes be tender to pressure.

The researchers in the study, led by Hugo Zeberg from Karolinska Institutet and Svante Pääbo from Max Planck Institute for Evolutionary Anthropology, set out to investigate whether genetic variants inherited from Neanderthals are involved in the disease.

Dupuytren’s disease is a fibrosing disorder of the palmar fascia, which may lead to an irreducible and disabling progressive flexion of the fingers.

Although the condition can affect any finger, the ring and middle fingers are most often afflicted.

Dupuytren’s disease is considered to be one of the most common hereditary disorders of the connective tissue, preferentially affecting individuals from Northern Europe.

After 60 years of age, its prevalence is high in Norway (46%), Scotland (39%), Iceland (33%) and Australia (28%).

Scientists have previously identified several risk factors for the condition, including age, alcohol consumption, diabetes, and genetic predisposition.

In 1999, a Danish study reported 80% heritability for the condition, indicating a strong genetic influence. The condition is much more common in people of Northern European ancestry.

“There are geographical differences in the extent of genetic ancestry linking present-day humans to now-extinct groups,” said Karolinska Institutet researcher Hugo Zeberg and colleagues.

“People from Africa south of the Sahara have little ancestry from Neanderthals or Denisovans, who that lived in Europe and Asia until at least 42,000 years ago.”

“In contrast, people with roots outside of Africa inherited as much as 2% of their genome from Neanderthals and some populations in Asia today have up to 5% Denisovan ancestry.”

“Given these regional differences, archaic gene variants can contribute to characteristics or diseases found primarily in certain populations.”

In their new research, the researchers aimed to investigate the genetic origins of Dupuytren’s disease.

They used data from 7,871 cases and 645,880 controls from the UK Biobank, the FinnGen R7 collection, and the Michigan Genomics Initiative to identify genetic risk variants for the disease.

They found 61 genome-wide significant variants associated with Dupuytren’s disease.

Further analysis showed that three of these variants are of Neanderthal origin, including the second and third most strongly associated ones.

The finding that two of the most important genetic risk factors for Dupuytren’s disease are of Neanderthal origin leads the scientists to conclude that Neanderthal ancestry is a significant factor in explaining the prevalence of the disease in Europe today.

Neanderthals lived in Europe and western Asia until about 40,000 years ago, when they were replaced by modern humans. However before Neanderthals disappeared, they mixed with modern humans. As a result, between one and two percent of the genomes of people with roots outside of Africa come from Neanderthals.

“Since Dupuytren's contracture is rarely seen in individuals of African descent, we wondered whether gene variants from Neanderthals can partly explain why people outside of Africa are affected”, says Hugo Zeberg, assistant professor at the department of Physiology and Pharmacology, Karolinska Institutet.

The researchers used data from three large clinical cohorts in the US, UK, and Finland, which allowed them to compare the genomes of 7,871 sufferers and 645,880 healthy controls. They identified 61 genetic risk factors for Dupuytren's contracture. The researchers found that three of these were inherited from Neanderthals, and these included the second and third most important risk factors.

The study is further evidence that the intermingling between Neanderthals and our ancestors has important consequences for the prevalence of some diseases, particularly among certain groups.

“This is a case where the meeting with Neanderthals has affected who suffers from illness, although we should not exaggerate the connection between Neanderthals and Vikings”, says Hugo Zeberg.

The study was financed by The Swedish Research Council, The Swedish Brain Foundation, The Erik Philip-Sörensen Foundation, Petrus och Augusta Hedlunds Stiftelse, and Emil och Wera Cornells Stiftelse.

Publication: “Major genetic risk factors for Dupuytren's disease are inherited from Neanderthals”, Richard Ågren, Snehal Patil, Xiang Zhou, FinnGen, Kristoffer Sahlholm, Svante Pääbo and Hugo Zeberg, Molecular Biology and Evolution, online June 14, 2023, doi: 10.1093/molbev/msad130

JOURNAL
Molecular Biology and Evolution

DOI
10.1093/molbev/msad130

Major Genetic Risk Factors for Dupuytren's Disease Are Inherited From Neandertals
Richard Ågren, Snehal Patil, Xiang Zhou, FinnGen. , Kristoffer Sahlholm, Svante Pääbo, Hugo Zeberg

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.

academic.oup.com/mbe/article/40/6/msad130/7197475

Last Edit: Jun 23, 2023 19:59:19 GMT by Admin

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Dupuytren's Disease Inherited From Neandertals Jun 22, 2023 18:58:47 GMT

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Post by Admin on Jun 22, 2023 18:58:47 GMT

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.

Introduction
Dupuytren's disease is a fibroproliferative disorder affecting the hand. Initially, nodules develop in the palmar fascia and thicken to form cords, leading to contractures causing fingers to become permanently bent in a flexed position. Although the condition can affect any finger, the ring and middle fingers are most often afflicted (Dutta et al. 2020). Several risk factors have been identified, including age, alcohol consumption, diabetes mellitus, and genetic predisposition (Rydberg et al. 2021). A Danish twin study reported 80% heritability (Larsen et al. 2015), indicating a strong genetic influence. One study estimated the prevalence of Dupuytren's disease among Norwegian individuals over 60 years to be ∼30% (Burge 1999). In contrast, Dupuytren's disease is less prevalent among individuals of primarily African descent. The geographic distribution has given Dupuytren's disease the nickname “Viking disease,” although this designation has been opposed (Ng et al. 2019).

In addition to case reports of Dupuytren's disease in Africa, one study measured the prevalence in a comparable fashion between different ancestries as a part of the Million Veteran Program (Saboeiro et al. 2000). In this study, the prevalence was 0.73% (95% confidence interval [CI]: 0.72–0.75%) among individuals of primarily European descent and 0.13% (95% CI: 0.12–0.14%) among individuals of primarily African descent. We note that a recent study (Salari et al. 2020), that suggested a high African prevalence, erroneously assigned diabetic patients from Jordan (Mustafa et al. 2016) and a small cohort of admixed individuals inhabiting the remote island Tristan da Cunha (Beighton and Valkenburg 1974), as individuals of African ancestry.

Genome-wide association studies (GWASs) have identified 36 risk variants for Dupuytren's disease, several of which are located in the proximity of genes encoding members of the profibrotic Wnt signaling pathway (Dolmans et al. 2011, ten Dam et al. 2016). The very high prevalence of Dupuytren's disease in certain populations, as noted above, indicates that common genetic variants may be powerful modulators of disease risk. Here, we perform a meta-analysis incorporating data from 3 large-scale biobanks, including 7,871 individuals with Dupuytren's disease and 645,880 controls, and identify 21 novel genetic risk variants. The rarity of the disease in African populations led us to investigate if any of the common variants are inherited from Neandertals, given that gene flow from Neandertals is limited in individuals of African ancestry (Chen et al. 2020). We find 3 risk factors for Dupuytren's disease inherited from Neandertals, 2 of which are the second and third major risk factors.

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Dupuytren's Disease Inherited From Neandertals Jun 23, 2023 19:57:55 GMT

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Post by Admin on Jun 23, 2023 19:57:55 GMT

Results
A Meta-analysis of Dupuytren's Disease Among 653,741 Europeans
We used 3 biobanks with individuals of primarily European descent, the UK Biobank (3,488 cases, 377,173 controls), FinnGen R7 (4,051 cases and 231,460 controls), and Michigan Genomics Initiative (MGI) freeze 3 (332 cases and 37,247 controls), to identify genetic risk variants for Dupuytren's disease. Analyzing the biobanks separately, we find 37 (UK Biobank), 19 (FinnGen), and 2 (MGI) haplotypes with genome-wide significance. To increase the statistical power, we performed a meta-analysis of the 3 biobanks based on single nucleotide variants present in all biobanks (N = 12,940,999 variants). To control for false positives, we calculated the genomic inflation factor which was found to be reasonable (λ = 1.10; supplementary fig. S1, Supplementary Material online). In total, we find 61 genetic loci of genome-wide significance (fig. 1; supplementary table S1, Supplementary Material online), out of which 24 are not significant in any biobank singly. The meta-analysis identifies 21 novel risk loci in addition to the ones previously identified by 2 GWASs (Dolmans et al. 2011, Ng et al. 2017).

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.

Neandertal Variants Increase the Risk for Dupuytren's Disease
First, we investigate the prevalence of Dupuytren's disease in individuals of European and African descent. In the MGI biobank, we find a Dupuytren's disease prevalence of 0.49% (95% CI: 0.26–0.83%) among individuals of primarily African ancestry, whereas the corresponding prevalence among individuals of primarily European ancestry is 1.37% (95% CI: 1.25–1.48%; t-test, 2-tailed, P = 0.00012). Similarly, a lower prevalence of Dupuytren's disease has been reported in the Million Veteran Program (Saboeiro et al. 2000) among individuals of primarily African ancestry (0.13%, 95% CI: 0.12–0.14%) compared with individuals of primarily European descent (0.73%, 95% CI: 0.72–0.75%). Taken together, European ancestry is associated with a higher risk for Dupuytren's disease than African ancestry (supplementary fig. S2, Supplementary Material online).

Given the rarity of Dupuytren's contracture among individuals of primarily African ancestry, we analyzed if any of the 61 risk loci harbor alleles inherited from Neandertals. We devised a novel algorithm, building on a recently described method (Chen et al. 2020), to identify archaic tracts in modern humans (see Materials and Methods). In brief, we identified haplotypes similar to the genomes of Neandertals and Denisovans (collectively referred to as “archaic humans”), now extinct human forms that lived in Western and Eastern Eurasia, respectively, until at least approximately ∼42,000 years ago (Devièse et al. 2021). We investigated whether such haplotypes overlapped with the most significant variant in each locus associated with Dupuytren's contracture and whether the most significant variant cosegregated with archaic haplotypes. Present-day genomes contain haplotypes that are similar to archaic genomes both because they inherited haplotypes from populations ancestral to both modern humans and archaic humans and because modern humans interbred with archaic groups when they met less than 100,000 years ago (Sankararaman et al. 2012). In order to restrict the analyses to recently introgressed archaic variants, we only considered haplotypes longer than 0.023 cM, which corresponds to a significance threshold of P < 0.05 for being derived from the ancestral population (adjusted for multiple comparisons; see Materials and Methods).

None of the loci harbored alleles that cosegregated (r2 > 0.2) with Denisovan haplotypes (supplementary table S2, Supplementary Material online). In contrast, we identified 3 loci in which the variant most significantly associated with Dupuytren's disease cosegregates with Neandertal haplotypes (r2 > 0.95, table 1). These loci include the second (rs17171240, chr7:37,984,972G/A, hg38, P = 6.4 × 10−132) and third (rs652483, chr8:69,142,848G/A, hg38, p = 9.2 × 10−69) most significant variants. In addition to these major risk factors, a third variant is also inherited from Neandertals (rs34017855, chr17:13,547,115C/T, hg38, p = 1.1 × 10−8). For these 3 variants, the most significant variant cosegregates with Neandertal haplotypes irrespectively of whether we use the “Altai” (Prüfer et al. 2014), the “Vindija” (Prüfer et al. 2017), or the “Chagyrskaya” (Mafessoni et al. 2020) Neandertal genomes. We find that for the variants on chromosome 7 and 8, using the “Altai” or “Chagyrskaya” Neandertal genomes as the introgressing Neandertal, result in a cosegregation of r2 > 0.95, but r2 = 0.72 and r2 = 0.35, respectively, using the “Vindija” genome (fig. 2; table 1). Thus, these 2 variants harbor Neandertal haplotypes more similar to the “Altai” and “Chagyrskaya” Neandertal genomes. For the variant on chromosome 17, we find a stronger cosegregation to the “Vindija” and “Chagyrskaya” Neandertal (r2 > 0.95) than for the “Altai” Neandertal genome (r2 = 0.84; table 1). Using the Denisovan genome (Meyer et al. 2012) as the introgressing archaic genome, we observe low correlations for all 61 variants influencing the risk for Dupuytren's disease (r2 < 0.2). However, we caution that IBDmix is not optimized for identifying haplotypes of Denisova origin (Chen et al. 2020). Since the choice of recombination map can influence the conclusion whether a haplotype is the result of gene flow or not, we substituted the African American-based recombination map (Zhou et al. 2020) for an Icelandic high-resolution recombination map (Halldorsson et al. 2019), or for a map inferred from identity-by-descent among European Americans (Zhou et al. 2020). We find Neandertal introgression in all 3 loci irrespective of recombination map used (supplementary tables S3 and S4, Supplementary Material online; see Materials and Methods).

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Dupuytren's Disease Inherited From Neandertals Jun 25, 2023 19:51:36 GMT

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Post by Admin on Jun 25, 2023 19:51:36 GMT

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.


Table 1.Neandertal-introgressed Risk Variants Associated With Dupuytren's Disease.
Chr	Position	Archaic haplotype LD r2(number)	Carriers 1000G (allele)	rsID	Reference allele	Alternative allele	OR (95% CI)
Vindija	Chagyrskaya	Altai	Denisova
7 	37,984,972 	0.72 (71) 	0.95 (93) 	0.95 (93) 	0.029 (4) 	96 (A) 	rs17171240 	G 	A 	1.79 (1.71–1.88) 
8 	69,142,848 	0.35 (29) 	0.73 (166) 	0.99 (229) 	0.000 (0) 	231 (G) 	rs652483 	G 	A 	0.72 (0.70–0.75) 
17 	13,547,115 	0.97 (131) 	0.96 (130) 	0.84 (117) 	0.001 (11) 	132 (T) 	rs34017855 	C 	T 	1.14 (1.09–1.20)


Table 2.Credible Set of Causal Variants in the Neandertal Haplotype.
Chr	Position	Ref	Alt	Anc.	Archaic	rsID	OR	P value	PIP	CADD	Reg. feature
7 	37,984,972 	G 	A 	G 	G/A 	rs17171240 	1.79 	6.4 × 10−132 	0.21 	7.3 	Open chromatin 
7 	37,984,802 	G 	A 	A 	G/A 	rs2044830 	1.79 	7.4 × 10−132 	0.18 	10.0 	Open chromatin 
7 	37,984,011 	T 	C 	T 	T/C 	rs117329120 	1.79 	8.2 × 10−132 	0.16 	1.1 	No overlap 
7 	37,983,798 	A 	G 	A 	A/G 	rs117575966 	1.79 	8.7 × 10−132 	0.15 	2.2 	No overlap 
7 	37,964,710 	G 	A 	G 	G/A 	rs117387543 	1.78 	2.0 × 10−131 	0.07 	1.5 	No overlap 
7 	37,964,701 	A 	G 	A 	A/G 	rs114929416 	1.78 	2.0 × 10−131 	0.06 	1.7 	No overlap 
7 	37,964,907 	A 	G 	A 	A/G 	rs79590116 	1.78 	2.0 × 10−131 	0.06 	4.5 	No overlap 
7 	37,966,121 	T 	A 	T 	T/A 	rs75182114 	1.77 	2.4 × 10−131 	0.06 	0.1 	No overlap 
7 	37,976,920 	T 	G 	T 	T/G 	rs74335252 	1.79 	2.5 × 10−131 	0.05 	2.1 	No overlap 
95% credible set derived from fine-mapping assuming one causal variant (Locuszoom; Pruim et al. 2010, Boughton et al. 2021). Archaic refers to alleles present in the Vindija, Chagyrskaya, and Altai Neandertal and Denisova genomes (Meyer et al. 2012, Prüfer et al. 2014, 2017, Mafessoni et al. 2020). Regulatory features are derived from Ensembl (Zerbino et al. 2015). Coordinates are in hg38.

Next, we evaluate if these Neandertal-derived haplotypes are associated with an increased risk, or protection against Dupuytren's disease. We find that all 3 Neandertal haplotypes are associated with an increased risk for Dupuytren's disease (table 1). Note, however, that for the chromosome 8 locus the G allele tagging the introgressed haplotypes in this locus is not observed in the sequenced Neandertal genomes. This variant is likely to represent an haplotype not yet sequenced from Neandertals. Another less likely possibility is that it is the result of a mutation early after introgression. Assuming a simple additive model, the combined odds ratio of carrying all 3 Neandertal risk alleles is 2.83 (95% CI = 2.62–3.05).

In a previous genome-wide scan (Racimo et al. 2017) the Neandertal haplotype associated with Dupuytren's disease on chromosome 8 has been identified as positively selected. It remains to be elucidated, however, what putatively positively selected trait this haplotypes might influence. In FinnGen and UK Biobank, this polymorphism is not associated with any trait other than Dupuytren's disease.

A rough calculation suggests that 8.4% of the heritability (h2) explained by the 61 genome-wide hits in our meta-analysis can be attributed to the 3 genetic risk factors of Neandertal origin (see Materials and Methods). In line with this, we find that the difference in polygenic risk score between cases and controls for Dupuytren's disease (see Materials and Methods) is reduced if the 3 loci harboring Neandertal haplotypes are removed from the analysis (supplementary fig. S3, Supplementary Material online).