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

Abstract

1Dupuytren's disease is the common inherited tissue-specific fibrotic disorder. It's characterized 2 by progressive and irreversible fibroblastic proliferation affecting the palmar fascia of the hand, 3 with an onset typically in the sixth decade of life. Although genome-wide association studies 4 (GWAS) have identified 24 genomic regions associated with Dupuytren's risk, the biological 5 mechanisms driving signal at these regions remain elusive. We identify potential biological 6 mechanisms for Dupuytren's disease by integrating the most recent, largest GWAS (݊ ௦ ௦ ൌ 7 ି ସ ), which suggests a shared genetic etiology. We further 15 refine the genome-wide genetic correlation signal to identify 8 regions significantly negatively 16 correlated with BMI and 3 regions significantly correlated (1 positively and 2 negatively 17 correlated) with HDL; none of these regions contained the novel gene association identified by 18 TWAS. Our results are consistent with previous epidemiological findings which show that lower 19 BMI increases risk for Dupuytren's disease. These 12 novel risk regions provide new insight into 20 the biological mechanisms of Dupuytren's disease and serve as a starting point for functional 21 validation. 22

The relationship between body mass index and the risk of development of Dupuytren’s disease: a Mendelian randomization study

“…Several epidemiological studies have reported that a high body mass index (BMI) is associated with a lower risk of DD (Gudmundsson et al., 2000; Hacquebord et al., 2017). This association is supported by a recent transcriptome-wide association study, which revealed a negative genetic correlation between BMI and DD risk (Major et al., 2019). However, the causal relationship for this correlation has yet to be explored, and no biological mechanisms have been proposed to explain how high BMI could protect against the development of DD.…”