Elaine Norton

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Journals/Publications

• Clark, B., Norton, E., Bamford, N., Randawa, I., Kemp, K., Bertin, F., & Stewart, A. (2024). Epidemiological investigation of insulin dysregulation in Shetland and Welsh ponies in Australia. Equine Veterinary Journal, 56(2). doi:10.1111/evj.14044
• Clark, B. L., Bamford, N. J., Stewart, A. J., McCue, M. E., Rendahl, A., Bailey, S. R., Bertin, F., & Norton, E. M. (2023).

  Evaluation of an HMGA2 variant contribution to height and basal insulin concentrations in ponies

  . Journal of Veterinary Internal Medicine, 37(3), 1186-1192. doi:10.1111/jvim.16723
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  Abstract Background The HMGA2 :c.83G>A variant was identified in Welsh ponies having pleiotropic effects on height and insulin concentration. Objective Determine whether the HMGA2 :c.83G>A variant is associated with decreased height and higher basal insulin concentrations across pony breeds. Animals Two hundred thirty‐six ponies across 6 breeds. Methods Cross‐sectional study. Ponies were genotyped for the HMGA2 :c.83G>A variant and phenotyped for height and basal insulin concentrations. Stepwise regression was performed for model analysis using a linear regression model for height and mixed linear model for insulin with farm as a random effect. Coefficient of determination, pairwise comparison of the estimated marginal means and partial correlation coefficients (parcor) were calculated to assess the relationship between HMGA2 genotype and height or insulin. Results Breed and genotype accounted for 90.5% of the variation in height across breeds, and genotype explained 21% to 44% of the variation within breeds. Breed, genotype, cresty neck score, sex, age, and farm accounted for 45.5% of the variation in insulin, with genotype accounting for 7.1%. The HMGA2 A allele frequency was 62% and correlated with both height (parcor = −0.39; P < .001) and insulin (parcor = 0.22; P = .02). Pairwise comparisons found A/A ponies were >10 cm shorter than other genotypes. Compared with G/G individuals, A/A and G/A individuals had 4.3 μIU/mL (95% confidence interval [CI]: 1.8‐10.5) and 2.7 μIU/mL (95% CI: 1.4‐5.3) higher basal insulin concentrations, respectively. Conclusions and Clinical Importance These data demonstrate the pleiotropic effects of the HMGA2 :c.83G>A variant and its role in identifying ponies at increased risk for insulin dysregulation.
• Manfredi, J. M., Jacob, S. I., Boger, B. L., & Norton, E. M. (2023). A one-health approach to identifying and mitigating the impact of endocrine disorders on human and equine athletes. American Journal of Veterinary Research, 1-15. doi:10.2460/ajvr.22.11.0194
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  Endocrinopathies affect multiple species in ever-increasing percentages of their populations, creating an opportunity to apply one-health approaches to determining creative preventative measures and therapies in athletes. Obesity and alterations in insulin and glucose dynamics are medical concerns that play a role in whole-body health and homeostasis in both horses and humans. The role and impact of endocrine disorders on the musculoskeletal, cardiovascular, and reproductive systems are of particular interest to the athlete. Elucidation of both physiologic and pathophysiologic mechanisms involved in disease processes, starting in utero, is important for development of prevention and treatment strategies for the health and well-being of all species. This review focuses on the unrecognized effects of endocrine disorders associated with the origins of metabolic disease; inflammation at the intersection of endocrine disease and related diseases in the musculoskeletal, cardiovascular, and reproductive systems; novel interventions; and diagnostics that are informed via multiomic and one-health approaches. Readers interested in further details on specific equine performance conditions associated with endocrine disease are invited to read the companion Currents in One Health by Manfredi et al, JAVMA, February 2023.
• Norton, E., Manfredi, J. M., & Jacob, S. (2023).

  A one-health lens offers new perspectives on the importance of endocrine disorders in the equine athlete

  . Journal of the American Veterinary Medical Association, 1-12. doi:10.2460/javma.22.11.0485
• Kingsley, N. B., Norton, E. M., Sandmeyer, L., Speed, D., Dwyer, A., Lassaline, M., McCue, M., & Bellone, R. R. (2022). Heritability of insidious uveitis in Appaloosa horses. Animal Genetics, 53(6), 872-877. doi:10.1111/age.13267
• Letko, A., Minor, K. M., Norton, E. M., Marinescu, M. D., Michaela, D., Ivansson, E., Megquier, K., Ji Noh, H., Starkey, M., Friedenberg, S., Lindblad-Toh, K., Mickelson, J., & Drogemuller, C. (2021). Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus. Genes (Basel), 12(12), 1964. doi:10.3390/genes12121964
• Norton, E., Minor, K. M., Taylor, S., McCue, M. E., & Mickelson, J. R. (2021).

  Heritability and Genomic Architecture of Episodic Exercise-Induced Collapse in Border Collies

  . Genes. doi:10.3390/genes12121927
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  An episodic nervous system disorder triggered by strenuous exercise, termed border collie collapse (BCC), exists in border collies and related breeds. The genetic basis of BCC is unknown but is believed to be a complex genetic disorder. Our goal was to estimate the heritability (h2SNP) of BCC, define its underlying genetic architecture, and identify associated genomic loci using dense whole-genome single-nucleotide polymorphism (SNP) genotyping data. Genotype data were obtained for ~440,000 SNPs from 343 border collies (168 BCC cases and 175 controls). h2SNP was calculated to be 49-61% depending on the estimated BCC prevalence. A total of 2407 SNPs across the genome accounted for nearly all the h2SNP of BCC, with an estimated 2003 SNPs of small effect, 349 SNPs of moderate effect, and 56 SNPs of large effect. Genome-wide association analyses identified significantly associated loci on chromosomes 1, 6, 11, 20, and 28, which accounted for ~5% of the total BCC h2SNP. We conclude that BCC is a moderately- to highly-heritable complex polygenetic disease resulting from contributions from hundreds to thousands of genetic variants with variable effect sizes. Understanding how much the BCC phenotype is determined by genetics and whether major gene mutations are likely to exist inform veterinarians and working/stock dog communities of the true nature of this condition.
• Norton, E., & McCue, M. E. (2020).

  Genetics of Equine Endocrine and Metabolic Disease

  . Veterinary Clinics of North America. doi:10.1016/j.cveq.2020.03.011
• Roy, M., Norton, E., Rendahl, A., Schultz, N., McFarlane, D., Geor, R. J., Mickelson, J. R., & McCue, M. E. (2020).

  Assessment of the FAM174A 11G allele as a risk allele for equine metabolic syndrome

  . Animal Genetics. doi:10.1111/age.12952
• Welch-Huston, B., Durward‐Akhurst, S. A., Norton, E., Ellingson, L. R., Rendahl, A., & McCue, M. E. (2020).

  Comparison between smartphone electrocardiography and standard three‐lead base apex electrocardiography in healthy horses

  . Veterinary Record. doi:10.1136/vr.105759
• Durward‐Akhurst, S. A., Schultz, N., Norton, E., Rendahl, A., Besselink, H., Behnisch, P. A., Brouwer, A., Geor, R. J., Mickelson, J. R., & McCue, M. E. (2019).

  Associations between endocrine disrupting chemicals and equine metabolic syndrome phenotypes

  . Chemosphere. doi:10.1016/j.chemosphere.2018.11.136
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  Equine Metabolic Syndrome (EMS) is characterized by abnormalities in insulin regulation, increased adiposity and laminitis, and has several similarities to human metabolic syndrome. A large amount of environmental variability in the EMS phenotype is not explained by commonly measured factors (diet, exercise, and season), suggesting that other environmental factors play a role in EMS development. Endocrine disrupting chemicals (EDCs) are associated with metabolic syndrome and other endocrine abnormalities in humans. This led us to hypothesize that EDCs are detectable in horse plasma and play a role in the pathophysiology of EMS. EDCs acting through the aryl hydrocarbon and estrogen receptors, were measured in plasma of 301 horses from 32 farms. The median (range) TEQ (2,3,7,8-TCDD equivalent) and EEQ (17β-estradiol equivalent) were 19.29 pg/g (0.59–536.36) and 10.50 pg/ml (4.35–15000.00), respectively. TEQ was negatively associated with plasma fat extracted and batch analyzed. EEQ was positively associated with pregnancy and batch analyzed, and negatively associated with being male and superfund score ≤100 miles of the farm. Of particular interest, serum glucose and insulin, glucose and insulin post oral sugar challenge, and leptin concentrations were associated with EEQ, and serum triglyceride concentration was associated with TEQ. Overall, we demonstrated that EDCs are present in the plasma of horses and may explain some of the environmental variability in measured EMS phenotypes. This is the first example of EDCs being associated with clinical disease phenotype components in domestic animals.
• Norton, E., Schultz, N., Geor, R. J., McFarlane, D., Mickelson, J. R., & McCue, M. E. (2019).

  Genome-Wide Association Analyses of Equine Metabolic Syndrome Phenotypes in Welsh Ponies and Morgan Horses

  . Genes. doi:10.3390/genes10110893
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  Equine metabolic syndrome (EMS) is a complex trait for which few genetic studies have been published. Our study objectives were to perform within breed genome-wide association analyses (GWA) to identify associated loci in two high-risk breeds, coupled with meta-analysis to identify shared and unique loci between breeds. GWA for 12 EMS traits identified 303 and 142 associated genomic regions in 264 Welsh ponies and 286 Morgan horses, respectively. Meta-analysis demonstrated that 65 GWA regions were shared across breeds. Region boundaries were defined based on a fixed-size or the breakdown of linkage disequilibrium, and prioritized if they were: shared between breeds or across traits (high priority), identified in a single GWA cohort (medium priority), or shared across traits with no SNPs reaching genome-wide significance (low priority), resulting in 56 high, 26 medium, and seven low priority regions including 1853 candidate genes in the Welsh ponies; and 39 high, eight medium, and nine low priority regions including 1167 candidate genes in the Morgans. The prioritized regions contained protein-coding genes which were functionally enriched for pathways associated with inflammation, glucose metabolism, or lipid metabolism. These data demonstrate that EMS is a polygenic trait with breed-specific risk alleles as well as those shared across breeds.
• McCoy, A. M., Norton, E., Kemper, A. M., Beeson, S. K., Mickelson, J. R., & McCue, M. E. (2018).

  SNP ‐based heritability and genetic architecture of tarsal osteochondrosis in North American Standardbred horses

  . Animal Genetics. doi:10.1111/age.12738
• Norton, E., Schultz, N., Rendahl, A., McFarlane, D., Geor, R. J., Mickelson, J. R., & McCue, M. E. (2018).

  Heritability of metabolic traits associated with equine metabolic syndrome in Welsh ponies and Morgan horses

  . Equine Veterinary Journal. doi:10.1111/evj.13053
• Norton, E., Avila, F., Schultz, N., Mickelson, J. R., & McCue, M. (2017). Identification of a genetic locus associated with height and metabolic traits in Welsh ponies. Journal of Veterinary Internal Medicine. doi:10.1016/j.jevs.2017.03.090
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  Donkeys are often kept, especially in industrialized countries, as companion animals. Donkeys have greater digestive efficiency and tend to expend less energy than horses or ponies, which contributes to obesity in nonworking donkeys. Obesity in all equine species increases risk of chronic health conditions such as laminitis and insulin resistance. Previous studies in horses and ponies have documented obesity's potential effects on glucose-insulin dynamics with lower insulin sensitivity and higher insulin responses to glucose. However, limited studies on obesity and its health impacts in donkeys exist, so these effects on glucose-insulin dynamics have not been fully studied. Twenty-four donkeys were selected according to initial body condition score (BCS) and divided into three categories with eight donkeys in each: thin, moderate, and obese. A frequently sampled glucose-insulin tolerance test was performed with subsequent MINMOD analysis to determine the effects of BCS on glucose-insulin dynamics. Basal insulin was highest in obese donkeys when compared with moderate and thin donkeys (P = .02 and P = .01, respectively). There was an overall trend across groups for BCS to lower insulin sensitivity (P = .06). No other effect was found. Body condition score seems to affect donkeys in a similar manner to horses and ponies as higher BCS was associated with higher basal insulin and may lower insulin sensitivity. Higher basal insulin concentrations in obese donkeys could negatively influence health and contribute to serious, chronic conditions.
• Norton, E., Mickelson, J. R., Binns, M. M., Blott, S., Caputo, P., Isgren, C. M., McCoy, A. M., Moore, A., Piercy, R. J., Swinburne, J., Vaudin, M. D., & McCue, M. E. (2016).

  Heritability of Recurrent Exertional Rhabdomyolysis in Standardbred and Thoroughbred Racehorses Derived From SNP Genotyping Data

  . Journal of Hereditary. doi:10.1093/jhered/esw042
• Norton, E., Wooldridge, A. A., Stewart, A. J., Cusimano, L., Schwartz, D. D., Johnson, C. M., Boudreaux, M. K., & Christopherson, P. W. (2016).

  Abnormal coagulation factor VIII transcript in a Tennessee Walking Horse colt with hemophilia A

  . Veterinary Clinical Pathology. doi:10.1111/vcp.12315
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  Hemophilia A is an X-chromosome-linked disorder caused by a deficiency in factor VIII (FVIII). Although foals have been diagnosed with hemophilia A based on deficiency in FVIII activity, causative gene mutations have not been identified. The genomic DNA and cDNA encoding FVIII of a Tennesee Walking Horse colt affected with hemophilia A and the genomic DNA of his dam and a normal unrelated horse were analyzed with no splice site or coding sequence abnormalities identified in any of the horses. Polymerase chain reactions (PCR) were then performed on hepatic cDNA from the affected colt and an unrelated normal horse, and no product was obtained for the sequence between and including exon 1 and exon 2 in the affected colt. Based on these results, suspected mutations were identified in the noncoding region of FVIII (intron 1), and genomic sequencing of intron 1 in the dam and the affected colt suggested maternal inheritance.

Proceedings Publications

• Norton, E., Avila, F., Schultz, N., Mickelson, J. R., Geor, R. J., & McCue, M. E. (2019).

  Evaluation of an HMGA2 variant for pleiotropic effects on height and metabolic traits in ponies

  . In American College of Veterinary Internal Medicine.
• McDonald, M. M., Norton, E., Schultz, N., Mickelson, J. R., & McCue, M. E. (2017).

  Association of leg length-to-torso ratios and metabolic phenotypes in Welsh ponies and Morgan horses

  . In Equine Science Society.
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  A truthful snapshot of horse welfare conditions is a prerequisite for predicting the impact of any actions intended to improve the quality of life of horses. This can be achieved when welfare information, gathered by different assessors in diverse geographical areas, is valid, comparable and collected in a harmonized way. This paper aims to present the first outcomes of the Animal Welfare Indicators (AWIN) approach: the results of on-farm assessment and a reliable and harmonized data collection system. A total of 355 sport and leisure horses, stabled in 40 facilities in Italy and in Germany, were evaluated by three trained assessors using the AWIN welfare assessment protocol for horses. The AWINHorse app was used to collect, store and send data to a common server. Identified welfare issues were obesity, unsatisfactory box dimensions, long periods of confinement and lack of social interaction. The digitalized data collection was feasible in an on-farm environment, and our results suggest that this approach could prove useful in identifying the most relevant welfare issues of horses in Europe or worldwide.

Presentations

• Norton, E. (2022, June). Clinical Applications of the Genetics of Equine Metabolic Syndrome. American College of Veterinary Internal Medicine Annual Forum. Austin, TX.
• Norton, E., McCarthy, H., Smalley, L., & Kent, M. (2022, June). Variability in Two Step Insulin Tolerance Test during Repeated Spring Testing. American College of Veterinary Internal Medicine Annual Forum. Austin, TX.
• Norton, E., Minor, K., Taylor, S., McCue, M., & Mickelson, J. (2022, Jan). Heritability and Genomic Architecture of Episodic Exercise-Induced Collapse in Border Collies.  Plant and Animal Genomics Conference. Plant and Animal Genomes Conference. San Diego, CA.
• Persoon, E., Norton, E., Karlsson, E., Durward-Akhurst, S., Mickelson, J., Tseng, A., & McCue, M. (2022, Oct). Investigation of Heritability of Behavioral Traits in Service Dogs. . International Conference on Canine and Feline Genetics and Genomics.. Huntsville, AL.