Integrative analysis of Dupuytren’s disease identifies novel risk locus and reveals a shared genetic etiology with BMI

Abstract

Dupuytrens disease is the common inherited tissue-specific fibrotic disorder. Its characterized by progressive and irreversible fibroblastic proliferation affecting the palmar fascia of the hand, with an onset typically in the sixth decade of life. Although genome-wide association studies (GWAS) have identified 24 genomic regions associated with Dupuytrens risk, the biological mechanisms driving signal at these regions remain elusive. We identify potential biological mechanisms for Dupuytrens disease by integrating the most recent, largest GWAS (ncases = 3,871, ncontrols = 4,686) with eQTLs (47 tissue panels from five consortia, total n = 3,975) to perform a transcriptome-wide association study (TWAS). We identify 43 tissue-specific gene associations with Dupuytrens risk, one of which resides at least 0.5 Mb away from the 24 risk regions previously identified. We also estimate the genome-wide genetic correlation between Dupuytrens disease and 45 complex traits and find significant genetic correlations between Dupuytrens disease and body mass index ([Formula], P = 1.6 x 10-6), type II diabetes ([Formula], P = 1.7 x 10-4), triglycerides ([Formula], P = 3.5 x 10-4), and high-density lipoprotein ([Formula], P = 4.1 x 10-4), which suggests a shared genetic etiology. We further refine the genome-wide genetic correlation signal to identify 8 regions significantly negatively correlated with BMI and 3 regions significantly correlated (1 positively and 2 negatively correlated) with HDL; none of these regions contained the novel gene association identified by TWAS. Our results are consistent with previous epidemiological findings which show that lower BMI increases risk for Dupuytrens disease. These 12 novel risk regions provide new insight into the biological mechanisms of Dupuytrens disease and serve as a starting point for functional validation.