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

Frontiers in Genetics

Genetics

Guilherme J. M. Rosa¹  Emily E. Binversie²  Susannah J. Sample²  Peter Muir²  Kiley Brauer²  Mehdi Momen²  Sabrina H. Brounts²  Margaret M. Patterson²  Brian W. Davis³  E. Gus Cothran³ 

[1] Department of Animal and Dairy Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI, United States;Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States;Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, United States;

关键词: degenerative suspensory ligament desmitis;    DSLD;    Peruvian Horse;    genome-wide association study;    GWAS;    genetic architecture;    polygenic risk score prediction;    biological pathways;   

DOI  :  10.3389/fgene.2023.1201628

 received in 2023-04-06, accepted in 2023-07-07,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: 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.Methods: 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.Results: 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 TGFB3 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 R2 on both the probit and logit liability scales, indicating a strong predictive performance.Discussion: 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.

【 授权许可】

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Copyright © 2023 Momen, Brauer, Patterson, Sample, Binversie, Davis, Cothran, Rosa, Brounts and Muir.