Studying the genetic basis of Dupuytren Disease is no different from studying the genetics of other human disorders. First of all, it requires a proper understanding of the clinical manifestations. A proper diagnosis is the foundation of a good human genetic study of a disorder; without this, a study is doomed to fail. A trained physician can readily make the Dupuytren diagnosis. The disease is a benign, chronic, slowly progressive disease affecting the hands. There is accumulation of fibrous tissue beneath the skin of the palm. This tissue shrinks along its length, pulling the fingers into a permanently bent position. Over time, Dupuytren contracture progresses toward a crippling deformity.

In addition to a proper diagnosis, for genetic studies we need to know more about the incidence of the disease, the age of onset, gender differences, and if there are known environmental risk factors for developing Dupuytren Disease. It would be helpful if tools are available to quantify disease severity or understand if there are other disorders that are comorbid with Dupuytren Disease. The big question for genetic studies, however, is the issue of heritability. Is there evidence that genetic factors do contribute to the disease? The measure to which extent genetic variation can explain phenotypic variation is captured by the heritability estimate. Heritability is a statistical measure to explain how much of the variation observed in a phenotype in a population is due to genetic variation in that population. A simple approach is to examine the familial occurrence and inheritance of Dupuytren Disease in order to get taste of the genetic contribution.

Dupuytren Disease has repeatedly been observed and described to occur in large families across different generation. The first substantial evidence that familial Dupuytren Disease may be a Mendelian trait, i.e., caused by a single genetic factor, transmitted from generation to generation in a pedigree, comes from a study a decade ago (Hu et al. 2005). A genetic linkage study was performed in a large Swedish family with Dupuytren Disease, resulting in the identification of a genetic disease locus on the long arm of chromosome 16. A genetic locus is a specific region on a chromosome and may contain multiple genes. Even though there was (and still is) no known gene with a mutation causing Dupuytren Disease, the genetic evidence showed that in this pedigree, Dupuytren Disease is inherited as an autosomal dominant trait.

Another important contribution to our understanding of the role of genetic factors and Dupuytren Disease came from a recent study by Becker et al. (2015). They examined a possible link between family history and disease severity of Dupuytren Disease. Individuals undergoing the first surgery for Dupuytren contracture were recruited (n = 801) without prior selection for family history. The mean age at first surgery was 59.0 ± 12.2 years of age with a range 22–87 years. Almost 40 % of probands reported a family history of the disease with a first-degree relative (i.e., parents or siblings) being affected. However, family history of the disease had the strongest effect on the age of first surgery. Affected individuals with a positive family history were on average 5.2 years younger than patients without known family history, a highly significant difference (p = 6.7E–08)². They also observed that the percentage of familial cases decreased with age of onset from 55 % in the 40–49 age category to 17 % for age 80 or older. Even though this study is not a population-based analysis and may be biased toward the most severe cases of DD, the results strongly suggest that a positive family history of the disease is the most prominent risk factor for surgical intervention at an earlier age.

Even though these studies point specifically toward a genetic contribution to disease, the question of heritability remained largely unanswered – until earlier this year. Larsen and colleagues performed the largest twin study of Dupuytren Disease thus far in a population-based twin registry in Denmark (Larsen et al. 2015). The size and scope of the study with >30,000 twins in the general population make this study very valuable for estimating the heritability and population prevalence of Dupuytren Disease. The difference in concordance rates of Dupuytren Disease in monozygotic and dizygotic twins yielded a heritability estimate of approximately 80 % with a prevalence of 0.6 % in the general population (Larsen et al. 2015). The high heritability means that much (but not all) of Dupuytren Disease in the population is due to genetic variation among individuals in that population. It does not necessarily mean that the genetic basis of the disease is simple, however.

These three studies (among some others) show that Dupuytren Disease is a highly heritable trait in which genetic factors are likely to play a role in disease severity. It also leaves room for other, nongenetic factors, such as environmental exposures to contribute as well. Sometimes Dupuytren Disease can manifest itself as a familial disorder inherited in a Mendelian fashion, as seen in the large Swedish family described above. This, however, is rarely the case. The emerging picture of the genetic architecture of Dupuytren Disease is very similar to other human complex traits in which there is a large contribution of many different genetic factors to the genetic risk of the disease (i.e., polygenicity), mixed with a smaller group of monogenic familial forms of the trait.

Even though the genetic evidence was limited a few years ago, we embarked on a genome-wide association study (GWAS) of Dupuytren Disease through a large collaborative effort (Dolmans et al. 2011). The purpose of a GWAS is to identify common risk alleles throughout the human genome contributing to a phenotype. Hundreds of thousands of locations in the genome are each examined for a possible link with disease. Success of a GWAS is largely dependent on sample size of the study since most common risk alleles have only a very modest effect on disease risk. To our surprise, we observed strong evidence of genetic risk factors for Dupuytren Disease, even though the discovery sample included <1,000 patients (Table 12.1). Probably the most exciting observation was that many of the nine loci that we identified contained genes known to be involved in Wnt signaling (Dolmans et al. 2011), pointing to a biological mechanism that is causally involved in the etiology of Dupuytren Disease. Wnt signaling is known to regulate the proliferation and differentiation of fibroblasts in both cancer and fibromatosis; the involvement of the Wnt signaling pathway in the pathogenesis of Dupuytren Disease is consistent with features of the disease and with established aspects of Wnt signaling. The first large-scale genetic study of Dupuytren Disease turned out to be very successful.