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A genome-wide association study demonstrates significant genetic variation for fracture risk in Thoroughbred racehorses.

Blott SC, Swinburne JE, Sibbons C, Fox-Clipsham LY, Helwegen M, Hillyer L, Parkin TD, Newton JR, Vaudin M - BMC Genomics (2014)

Bottom Line: Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31.Three SNPs on chromosome 18 (62.05 Mb - 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p < 0.05) in a genome-wide association study (GWAS).Two of the SNPs on ECA 18 were located in a haplotype block containing the gene zinc finger protein 804A (ZNF804A).

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Preventive Medicine, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk CB8 7UU, UK. sarah.blott@aht.org.uk.

ABSTRACT

Background: Thoroughbred racehorses are subject to non-traumatic distal limb bone fractures that occur during racing and exercise. Susceptibility to fracture may be due to underlying disturbances in bone metabolism which have a genetic cause. Fracture risk has been shown to be heritable in several species but this study is the first genetic analysis of fracture risk in the horse.

Results: Fracture cases (n = 269) were horses that sustained catastrophic distal limb fractures while racing on UK racecourses, necessitating euthanasia. Control horses (n = 253) were over 4 years of age, were racing during the same time period as the cases, and had no history of fracture at the time the study was carried out. The horses sampled were bred for both flat and National Hunt (NH) jump racing. 43,417 SNPs were employed to perform a genome-wide association analysis and to estimate the proportion of genetic variance attributable to the SNPs on each chromosome using restricted maximum likelihood (REML). Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31. Three SNPs on chromosome 18 (62.05 Mb - 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p < 0.05) in a genome-wide association study (GWAS). Two of the SNPs on ECA 18 were located in a haplotype block containing the gene zinc finger protein 804A (ZNF804A). One haplotype within this block has a protective effect (controls at 1.95 times less risk of fracture than cases, p = 1 × 10(-4)), while a second haplotype increases fracture risk (cases at 3.39 times higher risk of fracture than controls, p = 0.042).

Conclusions: Fracture risk in the Thoroughbred horse is a complex condition with an underlying genetic basis. Multiple genomic regions contribute to susceptibility to fracture risk. This suggests there is the potential to develop SNP-based estimators for genetic risk of fracture in the Thoroughbred racehorse, using methods pioneered in livestock genetics such as genomic selection. This information would be useful to racehorse breeders and owners, enabling them to reduce the risk of injury in their horses.

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Manhattan plots of raw and corrected p-values from the genome-wide association (CMH test) for whole genome and ECA 18. (a) Manhattan plot of raw p-values from the genome-wide association analysis (CMH test) with flat and National Hunt-bred horses combined. (b) Manhattan plot of empirical p-values, calculated after 1000 permutations (c) empirical p-values for ECA 18 plotted against SNP position on the chromosome (Mb). The 5% genome-wide significance threshold is shown as a red line.
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Figure 1: Manhattan plots of raw and corrected p-values from the genome-wide association (CMH test) for whole genome and ECA 18. (a) Manhattan plot of raw p-values from the genome-wide association analysis (CMH test) with flat and National Hunt-bred horses combined. (b) Manhattan plot of empirical p-values, calculated after 1000 permutations (c) empirical p-values for ECA 18 plotted against SNP position on the chromosome (Mb). The 5% genome-wide significance threshold is shown as a red line.

Mentions: Three SNPs on ECA 18 and one on ECA 1, reached genome-wide significance after correction for multiple testing (pgenome < 0.05) Table 2. ECA 18 showed evidence for more than one SNP associated with distal limb fracture. A number of supporting SNPs are seen, with the peak localizing to around 62 Mb. There is also evidence of suggestive signals seen on ECA 3, 8, 9, 15, 21 and 22 although they do not reach genome-wide significance level. Figure 1 shows Manhattan plots of (a) the raw p-values from the genome-wide association (Cochran-Mantel-Haenszel) scan for distal limb fracture (b) empirical p-values, calculated after 1000 permutations (c) empirical p-values for ECA 18. The additional 78 SNPs on ECA 18, genotyped for fine mapping purposes, showed no significant associations with fracture risk and did not explain any more of the genetic variation in the heritability analysis than the SNPs included on the Equine SNP50 BeadChip.


A genome-wide association study demonstrates significant genetic variation for fracture risk in Thoroughbred racehorses.

Blott SC, Swinburne JE, Sibbons C, Fox-Clipsham LY, Helwegen M, Hillyer L, Parkin TD, Newton JR, Vaudin M - BMC Genomics (2014)

Manhattan plots of raw and corrected p-values from the genome-wide association (CMH test) for whole genome and ECA 18. (a) Manhattan plot of raw p-values from the genome-wide association analysis (CMH test) with flat and National Hunt-bred horses combined. (b) Manhattan plot of empirical p-values, calculated after 1000 permutations (c) empirical p-values for ECA 18 plotted against SNP position on the chromosome (Mb). The 5% genome-wide significance threshold is shown as a red line.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4008154&req=5

Figure 1: Manhattan plots of raw and corrected p-values from the genome-wide association (CMH test) for whole genome and ECA 18. (a) Manhattan plot of raw p-values from the genome-wide association analysis (CMH test) with flat and National Hunt-bred horses combined. (b) Manhattan plot of empirical p-values, calculated after 1000 permutations (c) empirical p-values for ECA 18 plotted against SNP position on the chromosome (Mb). The 5% genome-wide significance threshold is shown as a red line.
Mentions: Three SNPs on ECA 18 and one on ECA 1, reached genome-wide significance after correction for multiple testing (pgenome < 0.05) Table 2. ECA 18 showed evidence for more than one SNP associated with distal limb fracture. A number of supporting SNPs are seen, with the peak localizing to around 62 Mb. There is also evidence of suggestive signals seen on ECA 3, 8, 9, 15, 21 and 22 although they do not reach genome-wide significance level. Figure 1 shows Manhattan plots of (a) the raw p-values from the genome-wide association (Cochran-Mantel-Haenszel) scan for distal limb fracture (b) empirical p-values, calculated after 1000 permutations (c) empirical p-values for ECA 18. The additional 78 SNPs on ECA 18, genotyped for fine mapping purposes, showed no significant associations with fracture risk and did not explain any more of the genetic variation in the heritability analysis than the SNPs included on the Equine SNP50 BeadChip.

Bottom Line: Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31.Three SNPs on chromosome 18 (62.05 Mb - 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p < 0.05) in a genome-wide association study (GWAS).Two of the SNPs on ECA 18 were located in a haplotype block containing the gene zinc finger protein 804A (ZNF804A).

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Preventive Medicine, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk CB8 7UU, UK. sarah.blott@aht.org.uk.

ABSTRACT

Background: Thoroughbred racehorses are subject to non-traumatic distal limb bone fractures that occur during racing and exercise. Susceptibility to fracture may be due to underlying disturbances in bone metabolism which have a genetic cause. Fracture risk has been shown to be heritable in several species but this study is the first genetic analysis of fracture risk in the horse.

Results: Fracture cases (n = 269) were horses that sustained catastrophic distal limb fractures while racing on UK racecourses, necessitating euthanasia. Control horses (n = 253) were over 4 years of age, were racing during the same time period as the cases, and had no history of fracture at the time the study was carried out. The horses sampled were bred for both flat and National Hunt (NH) jump racing. 43,417 SNPs were employed to perform a genome-wide association analysis and to estimate the proportion of genetic variance attributable to the SNPs on each chromosome using restricted maximum likelihood (REML). Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31. Three SNPs on chromosome 18 (62.05 Mb - 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p < 0.05) in a genome-wide association study (GWAS). Two of the SNPs on ECA 18 were located in a haplotype block containing the gene zinc finger protein 804A (ZNF804A). One haplotype within this block has a protective effect (controls at 1.95 times less risk of fracture than cases, p = 1 × 10(-4)), while a second haplotype increases fracture risk (cases at 3.39 times higher risk of fracture than controls, p = 0.042).

Conclusions: Fracture risk in the Thoroughbred horse is a complex condition with an underlying genetic basis. Multiple genomic regions contribute to susceptibility to fracture risk. This suggests there is the potential to develop SNP-based estimators for genetic risk of fracture in the Thoroughbred racehorse, using methods pioneered in livestock genetics such as genomic selection. This information would be useful to racehorse breeders and owners, enabling them to reduce the risk of injury in their horses.

Show MeSH
Related in: MedlinePlus