Biologically Enhanced Genome-Wide Association Study Provides Further Evidence for Candidate Loci and Discovers Novel Loci That Influence Risk of Anterior Cruciate Ligament Rupture in a Dog Model.

Autor:	Baker LA; Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States., Momen M; Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States., McNally R; Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States., Berres ME; Bioinformatics Resource Center, Biotechnology Center, University of Wisconsin-Madison, Madison, WI, United States., Binversie EE; Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States., Sample SJ; Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States., Muir P; Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in genetics [Front Genet] 2021 Mar 05; Vol. 12, pp. 593515. Date of Electronic Publication: 2021 Mar 05 (Print Publication: 2021).
DOI:	10.3389/fgene.2021.593515
Abstrakt:	Anterior cruciate ligament (ACL) rupture is a common condition that disproportionately affects young people, 50% of whom will develop knee osteoarthritis (OA) within 10 years of rupture. ACL rupture exhibits both hereditary and environmental risk factors, but the genetic basis of the disease remains unexplained. Spontaneous ACL rupture in the dog has a similar disease presentation and progression, making it a valuable genomic model for ACL rupture. We leveraged the dog model with Bayesian mixture model (BMM) analysis (BayesRC) to identify novel and relevant genetic variants associated with ACL rupture. We performed RNA sequencing of ACL and synovial tissue and assigned single nucleotide polymorphisms (SNPs) within differentially expressed genes to biological prior classes. SNPs with the largest effects were on chromosomes 3, 5, 7, 9, and 24. Selection signature analysis identified several regions under selection in ACL rupture cases compared to controls. These selection signatures overlapped with genome-wide associations with ACL rupture as well as morphological traits. Notable findings include differentially expressed ACSF3 with MC1R (coat color) and an association on chromosome 7 that overlaps the boundaries of SMAD2 (weight and body size). Smaller effect associations were within or near genes associated with regulation of the actin cytoskeleton and the extracellular matrix, including several collagen genes. The results of the current analysis are consistent with previous work published by our laboratory and others, and also highlight new genes in biological pathways that have not previously been associated with ACL rupture. The genetic associations identified in this study mirror those found in human beings, which lays the groundwork for development of disease-modifying therapies for both species. Competing Interests: The authors of this manuscript have the following competing interests: PM, LB and MM are named on US Patent US20160222451A1 “Method to predict heritable canine non-contact cruciate ligament rupture.” This does not alter our adherence to the journal’s policies on data sharing and materials. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Baker, Momen, McNally, Berres, Binversie, Sample and Muir.)
Databáze:	MEDLINE
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