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Genet Epidemiol. 2019 May 13. doi: 10.1002/gepi.22209. [Epub ahead of print]

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

Author information

1
Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, California.
2
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
3
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
4
Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Oxford, UK.
5
Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
6
NIHR Biomedical Research Centre, NDORMS, University of Oxford, Oxford, UK.
7
Department of Biomathematics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
8
Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, California.

Abstract

Dupuytren's disease is a common inherited tissue-specific fibrotic disorder, characterized by progressive and irreversible fibroblastic proliferation affecting the palmar fascia of the hand. Although genome-wide association study (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 Dupuytren's disease by integrating the most recent, largest GWAS (3,871 cases and 4,686 controls) with eQTLs (47 tissue panels from five consortia, total n = 3,975) to perform a transcriptome-wide association study. We identify 43 tissue-specific gene associations with Dupuytren's risk, including one in a novel risk region. We also estimate the genome-wide genetic correlation between Dupuytren's disease and 45 complex traits and find significant genetic correlations between Dupuytren's disease and body mass index (BMI), type II diabetes, triglycerides, and high-density lipoprotein (HDL), suggesting a shared genetic etiology between these traits. We further examine local genetic correlation to identify 8 and 3 novel regions significantly correlated with BMI and HDL respectively. Our results are consistent with previous epidemiological findings showing that lower BMI increases risk for Dupuytren's disease. These 12 novel risk regions provide new insight into the biological mechanisms of Dupuytren's disease and serve as a starting point for functional validation.

KEYWORDS:

Dupuytren's disease; body mass index; complex traits; fibrosis; genetic correlation; high-density lipoprotein; transcriptome-wide association study

PMID:
31087417
DOI:
10.1002/gepi.22209

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