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Frontiers in genetics2023; 14; 1201628; doi: 10.3389/fgene.2023.1201628

Genetic architecture and polygenic risk score prediction of degenerative suspensory ligament desmitis (DSLD) in the Peruvian Horse.

Abstract: Spontaneous rupture of tendons and ligaments is common in several species including humans. In horses, degenerative suspensory ligament desmitis (DSLD) is an important acquired idiopathic disease of a major energy-storing tendon-like structure. DSLD risk is increased in several breeds, including the Peruvian Horse. Affected horses have often been used for breeding before the disease is apparent. Breed predisposition suggests a substantial genetic contribution, but heritability and genetic architecture of DSLD have not been determined. To identify genomic regions associated with DSLD, we recruited a reference population of 183 Peruvian Horses, phenotyped as DSLD cases or controls, and undertook a genome-wide association study (GWAS), a regional window variance analysis using local genomic partitioning, a signatures of selection (SOS) analysis, and polygenic risk score (PRS) prediction of DSLD risk. We also estimated trait heritability from pedigrees. Heritability was estimated in a population of 1,927 Peruvian horses at 0.22 ± 0.08. After establishing a permutation-based threshold for genome-wide significance, 151 DSLD risk single nucleotide polymorphisms (SNPs) were identified by GWAS. Multiple regions of enriched local heritability were identified across the genome, with strong enrichment signals on chromosomes 1, 2, 6, 10, 13, 16, 18, 22, and the X chromosome. With SOS analysis, there were 66 genes with a selection signature in DSLD cases that was not present in the control group that included the gene. Pathways enriched in DSLD cases included proteoglycan metabolism, extracellular matrix homeostasis, and signal transduction pathways that included the hedgehog signaling pathway. The best PRS predictive performance was obtained when we fitted 1% of top SNPs using a Bayesian Ridge Regression model which achieved the highest mean of R on both the probit and logit liability scales, indicating a strong predictive performance. We conclude that within-breed GWAS of DSLD in the Peruvian Horse has further confirmed that moderate heritability and a polygenic architecture underlies the trait and identified multiple DSLD SNP associations in novel tendinopathy candidate genes influencing disease risk. Pathways enriched with DSLD risk variants include ones that influence glycosaminoglycan metabolism, extracellular matrix homeostasis, signal transduction pathways.
Copyright © 2023 Momen, Brauer, Patterson, Sample, Binversie, Davis, Cothran, Rosa, Brounts and Muir.
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Publication Date: 2023-08-14 PubMed ID: 37645058PubMed Central: PMC10460910DOI: 10.3389/fgene.2023.1201628Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research aims to understand the genetic factors that affect horses’ risk for developing degenerative suspensory ligament desmitis (DSLD), a degenerative tendon disease. Using a variety of genetic analysis methods on a pool of 183 Peruvian Horses, the team identified associated genomic regions, estimated the trait’s heritability, and created a polygenic risk score model to predict DSLD risk.

Overview of the Study

  • The researchers gathered a reference population of 183 Peruvian Horses, identified as either having DSLD (the cases) or not (the controls). The Peruvian Horse was chosen due to the breed’s increased predisposition to DSLD.
  • Using this population, they performed different forms of genetic analysis: a genome-wide association study (GWAS), a regional window variance analysis using local genome partitioning, a signatures of selection (SOS) analysis, and computed polygenic risk scores (PRS) for predicting DSLD risk.
  • Besides this, the researchers estimated the trait heritability from pedigrees, using a larger population pool of 1,927 Peruvian horses.

Findings of the Study

  • The trait’s heritability was calculated to be 0.22 ± 0.08. Heritability, in this context, refers to the extent that genetic variation can explain the observed variation in DSLD occurrence among the Peruvian Horse population.
  • After setting a threshold for genome-wide significance, GWAS identified 151 risk single nucleotide polymorphisms (SNPs, variations in a single base pair in a DNA sequence) associated with DSLD.
  • There were multiple regions across the genome showing enriched local heritability, particularly on chromosomes 1, 2, 6, 10, 13, 16, 18, 22, and the X chromosome. “Enriched local heritability” implies these chromosomal regions contribute more to the heritability of DSLD.
  • The SOS analysis revealed 66 genes that had selection signatures in DSLD cases, which did not appear in the control group. A selection signature indicates these genes were subjected to selection, suggesting they contribute to disease susceptibility.
  • Pathways enriched in DSLD cases were related to proteoglycan metabolism, extracellular matrix homeostasis, and certain signal transduction pathways, including the “hedgehog” signaling pathway. These are biological process and actions that, when disrupted, may negatively impact tendon health.

Polygenic Risk Score

  • The team developed a predictive model using PRS, fitting the top 1% of SNPs through a Bayesian Ridge Regression model.
  • This model showed strong predictive performance for DSLD risk, evidenced by a high mean R-value on both probit and logit liability scales. The higher the R-value, the more accurately the model predicts the outcome (DSLD risk).

In conclusion, the study reveals that DSLD in Peruvian Horses has a moderate heritability and polygenic architecture. The researchers were able to pinpoint multiple SNP associations in novel tendinopathy candidate genes influencing disease risk, opening avenues for further genetic study and potential preventative measures.

Cite This Article

APA
Momen M, Brauer K, Patterson MM, Sample SJ, Binversie EE, Davis BW, Cothran EG, Rosa GJM, Brounts SH, Muir P. (2023). Genetic architecture and polygenic risk score prediction of degenerative suspensory ligament desmitis (DSLD) in the Peruvian Horse. Front Genet, 14, 1201628. https://doi.org/10.3389/fgene.2023.1201628

Publication

Frontiers in genetics
ISSN: 1664-8021
NlmUniqueID: 101560621
Country: Switzerland
Language: English
Volume: 14
Pages: 1201628
PII: 1201628

Researcher Affiliations

Momen, Mehdi
  • Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States.
Brauer, Kiley
  • Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States.
Patterson, Margaret M
  • Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States.
Sample, Susannah J
  • Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States.
Binversie, Emily E
  • Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States.
Davis, Brian W
  • Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, United States.
Cothran, E Gus
  • Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, United States.
Rosa, Guilherme J M
  • Department of Animal and Dairy Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI, United States.
Brounts, Sabrina H
  • Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States.
Muir, Peter
  • Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States.

Conflict of Interest Statement

PM, MM, SS, and SB are involved in setting up a genetic screening test for risk of DSLD in the Peruvian Horse at the University of Wisconsin-Madison. 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.

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Citations

This article has been cited 1 times.
  1. Guest DJ, Birch HL, Thorpe CT. A review of the equine suspensory ligament: Injury prone yet understudied. Equine Vet J 2025 Sep;57(5):1167-1182.
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