Identification of Genetic Variants Associated with Anterior Cruciate Ligament Rupture and AKC Standard Coat Color in the Labrador Retriever

Overview

Journal BMC Genom Data

Publisher Biomed Central

Specialty Genetics

Date 2023 Oct 26

PMID 37884875

Authors

B T Lee

L A Baker

M Momen

H Terhaar

E E Binversie

S J Sample

Peter Muir

Affiliations

Soon will be listed here.

Abstract

Canine anterior cruciate ligament (ACL) rupture is a common complex disease. Prevalence of ACL rupture is breed dependent. In an epidemiological study, yellow coat color was associated with increased risk of ACL rupture in the Labrador Retriever. ACL rupture risk variants may be linked to coat color through genetic selection or through linkage with coat color genes. To investigate these associations, Labrador Retrievers were phenotyped as ACL rupture case or controls and for coat color and were single nucleotide polymorphism (SNP) genotyped. After filtering, ~ 697 K SNPs were analyzed using GEMMA and mvBIMBAM for multivariate association. Functional annotation clustering analysis with DAVID was performed on candidate genes. A large 8 Mb region on chromosome 5 that included ACSF3, as well as 32 additional SNPs, met genome-wide significance at P < 6.07E-7 or Log(BF) = 3.0 for GEMMA and mvBIMBAM, respectively. On chromosome 23, SNPs were located within or near PCCB and MSL2. On chromosome 30, a SNP was located within IGDCC3. SNPs associated with coat color were also located within ADAM9, FAM109B, SULT1C4, RTDR1, BCR, and RGS7. DZIP1L was associated with ACL rupture. Several significant SNPs on chromosomes 2, 3, 7, 24, and 26 were located within uncharacterized regions or long non-coding RNA sequences. This study validates associations with the previous ACL rupture candidate genes ACSF3 and DZIP1L and identifies novel candidate genes. These variants could act as targets for treatment or as factors in disease prediction modeling. The study highlighted the importance of regulatory SNPs in the disease, as several significant SNPs were located within non-coding regions.

References

Nunes-Santos C, Uzel G, Rosenzweig S . PI3K pathway defects leading to immunodeficiency and immune dysregulation. J Allergy Clin Immunol. 2019; 143(5):1676-1687. DOI: 10.1016/j.jaci.2019.03.017. View

Lai Z, Moravcova S, Canitrot Y, Andrzejewski L, Walshe D, Rea S . Msl2 is a novel component of the vertebrate DNA damage response. PLoS One. 2013; 8(7):e68549. PMC: 3706407. DOI: 10.1371/journal.pone.0068549. View

Collins F, Williams J, Bloom A, Singh R, Jordan L, Stone M . CCL3 and MMP-9 are induced by TL1A during death receptor 3 (TNFRSF25)-dependent osteoclast function and systemic bone loss. Bone. 2017; 97:94-104. PMC: 5378198. DOI: 10.1016/j.bone.2017.01.002. View

Kim S, Brossard M, Roshandel D, Paterson A, Bull S, Yoo Y . gpart: human genome partitioning and visualization of high-density SNP data by identifying haplotype blocks. Bioinformatics. 2019; 35(21):4419-4421. PMC: 6821423. DOI: 10.1093/bioinformatics/btz308. View

Karlsson E, Lindblad-Toh K . Leader of the pack: gene mapping in dogs and other model organisms. Nat Rev Genet. 2008; 9(9):713-25. DOI: 10.1038/nrg2382. View

Sellon D, Marcellin-Little D . Risk factors for cranial cruciate ligament rupture in dogs participating in canine agility. BMC Vet Res. 2022; 18(1):39. PMC: 8760802. DOI: 10.1186/s12917-022-03146-2. View

Zhang T, Yang Y, Yin X, Wang X, Ni J, Dong Z . Two loss-of-function ANKRD11 variants in Chinese patients with short stature and a possible molecular pathway. Am J Med Genet A. 2020; 185(3):710-718. PMC: 7898801. DOI: 10.1002/ajmg.a.62024. View

Everts R, Rothuizen J, van Oost B . Identification of a premature stop codon in the melanocyte-stimulating hormone receptor gene (MC1R) in Labrador and Golden retrievers with yellow coat colour. Anim Genet. 2000; 31(3):194-9. DOI: 10.1046/j.1365-2052.2000.00639.x. View

Hohos N, Smith A, Kilaru V, Park H, Hausman D, Bailey L . CD4 and CD8 T-Cell-Specific DNA Cytosine Methylation Differences Associated With Obesity. Obesity (Silver Spring). 2018; 26(8):1312-1321. PMC: 6107382. DOI: 10.1002/oby.22225. View

10.

Bartok B, Boyle D, Liu Y, Ren P, Ball S, Bugbee W . PI3 kinase δ is a key regulator of synoviocyte function in rheumatoid arthritis. Am J Pathol. 2012; 180(5):1906-16. DOI: 10.1016/j.ajpath.2012.01.030. View

11.

Lu H, Galeano M, Ott E, Kaeslin G, Kausalya P, Kramer C . Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nat Genet. 2017; 49(7):1025-1034. PMC: 5687889. DOI: 10.1038/ng.3871. View

12.

Carter D, Sood R, Seaton M, Muffley L, Honari S, Hocking A . MC1R gene polymorphisms are associated with dysfunctional immune responses and wound infection after burn injury. J Surg Res. 2018; 231:448-452. PMC: 6464811. DOI: 10.1016/j.jss.2018.07.018. View

13.

Bartok B, Hammaker D, Firestein G . Phosphoinositide 3-kinase δ regulates migration and invasion of synoviocytes in rheumatoid arthritis. J Immunol. 2014; 192(5):2063-70. DOI: 10.4049/jimmunol.1300950. View

14.

Elkin S, Lakoduk A, Schmid S . Endocytic pathways and endosomal trafficking: a primer. Wien Med Wochenschr. 2016; 166(7-8):196-204. PMC: 4873410. DOI: 10.1007/s10354-016-0432-7. View

15.

Baird A, Carter S, Innes J, Ollier W, Short A . Genome-wide association study identifies genomic regions of association for cruciate ligament rupture in Newfoundland dogs. Anim Genet. 2014; 45(4):542-9. DOI: 10.1111/age.12162. View

16.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

17.

Binversie E, Walczak B, Cone S, Baker L, Scerpella T, Muir P . Canine ACL rupture: a spontaneous large animal model of human ACL rupture. BMC Musculoskelet Disord. 2022; 23(1):116. PMC: 8818196. DOI: 10.1186/s12891-021-04986-z. View

18.

Browning B, Zhou Y, Browning S . A One-Penny Imputed Genome from Next-Generation Reference Panels. Am J Hum Genet. 2018; 103(3):338-348. PMC: 6128308. DOI: 10.1016/j.ajhg.2018.07.015. View

19.

Stephens M . A unified framework for association analysis with multiple related phenotypes. PLoS One. 2013; 8(7):e65245. PMC: 3702528. DOI: 10.1371/journal.pone.0065245. View

20.

Xu J, Jiang C, Cai Y, Guo Y, Wang X, Zhang J . Intervening upregulated SLC7A5 could mitigate inflammatory mediator by mTOR-P70S6K signal in rheumatoid arthritis synoviocytes. Arthritis Res Ther. 2020; 22(1):200. PMC: 7457370. DOI: 10.1186/s13075-020-02296-8. View