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

Abstract

Background Ponies are highly susceptible to metabolic derangements including hyperinsulinemia, insulin resistance, and adiposity. Hypothesis/Objectives Genetic loci affecting height in ponies have pleiotropic effects on metabolic pathways and increase the susceptibility to equine metabolic syndrome (EMS). Animals Two hundred ninety‐four Welsh ponies and 529 horses. Methods Retrospective study of horses phenotyped for metabolic traits. Correlations between height and metabolic traits were assessed by Pearson's correlation coefficients. Complementary genome‐wide analysis methods were used to identify a region of interest (ROI) for height and metabolic traits, determine the fraction of heritability contributed by the ROI, and identify candidate genes. Results There was an inverse relationship between height and baseline insulin (−0.26) in ponies. Genomic signature of selection and association analyses for both height and insulin identified the same ~1.3 megabase region on chromosome 6 that contained a shared ancestral haplotype between these traits. The ROI contributed ~40% of the heritability for height and ~20% of the heritability for insulin. High‐mobility group AT‐hook 2 was identified as a candidate gene, and Sanger sequencing detected a c.83G>A (p.G28E) variant associated with height in Shetland ponies. In our cohort of ponies, the A allele had a frequency of 0.76, was strongly correlated with height (−0.75), and was low to moderately correlated with metabolic traits including: insulin (0.32), insulin after an oral sugar test (0.25), non‐esterified fatty acids (0.19), and triglyceride (0.22) concentrations. Conclusions and Clinical Importance These data have important implications for identifying individuals at risk for EMS.

Identification of Novel lncRNAs Differentially Expressed in Placentas of Chinese Ningqiang Pony and Yili Horse Breeds

“…As a core transcription factor in embryonic stem cells, ZNF281 (zinc finger protein 281) was found to be related to spontaneous osteochondrogenic differentiation [38]. Other studies showed the strong association of LCORL/NCAPG, HMGA2, PROP1, LASP [39], ZFAT, DIAPH3 [40], ACTN2, ADAMTS17, GH1, ANKRD1 [40], and ACAN [41,42] with miniature size and dwarfism in a variety of pony breeds, including Shetland [41,43], miniature [44], Welsh ponies [45], German warmblood horses [46], American miniature horses, Brazilian ponies [47], and Jeju ponies [48], as well as B4GALT7 [49] and PROP1 [50] in Friesian horses. These genes were not found in this study, which may be due to the expression specificity of lncRNAs in different horse breeds [27] and different omics levels, since TBX3, under strong selection in Chinese ponies, was also identified in this study.…”

Genome-Wide Homozygosity Patterns and Evidence for Selection in a Set of European and Near Eastern Horse Breeds

“…Additionally, the 662 kb long ROH island on ECA6 in Exmoor Pony at position 81.12-81.80 Mb harboring the genes HMGA2 , LLPH , IRAK3 and HELB supports these considerations. Norton et al [83] identified ancestral haplotypes between ECA6:81.16-81.58 associated with height and baseline insulin values in Welsh ponies and supposed HMGA2 and IRAK3 as candidate genes involved in the equine metabolic syndrome.…”

HMGA Genes and Proteins in Development and Evolution

“…Several genome-wide association studies (GWAS) have outlined HMGA2 as an important factor in determining dimensions in humans, horses and dogs [90][91][92][93][94][95][96][97][98][99][100][101]. Furthermore, Hmga2 mutations have been involved in Silver-Russell syndrome (SRS), or SRS-like syndromes [102][103][104], or ear dimensions in pigs [105].…”