A genome-wide association study identifies novel candidate genes for susceptibility to diabetes mellitus in non-obese cats

• Published in: PloS one Vol. 16; no. 12; p. e0259939
• Main Authors: Forcada, Yaiza, Boursnell, Mike, Catchpole, Brian, Church, David B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.12.2021; Public Library of Science (PLoS)
• Subjects: Animals; Beta cells; Biology and Life Sciences; Case-Control Studies; Cat Diseases - genetics; Cats; Chromosome Mapping; Chromosomes; Data analysis; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus - genetics; Diabetes Mellitus - veterinary; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics; Disease; Disease susceptibility; DNA; Domestic animals; Endocrine disorders; Environmental factors; Epigenetics; Evaluation; Female; Gene polymorphism; Genes; Genetic Predisposition to Disease; Genetic testing; Genome-wide association studies; Genome-Wide Association Study - veterinary; Genomes; Haplotypes; Health aspects; Health risk assessment; Hyperglycemia; Inactivation; Insulin; Insulin resistance; Insulin-like growth factors; Lipids; Male; Medicine and Health Sciences; Membrane Proteins - genetics; Metabolism; Obesity; Peptidase; Peptidases; Polymorphism; Polymorphism, Single Nucleotide; Population; Population structure; Protein Tyrosine Phosphatases - genetics; Quality control; Risk factors; Single-nucleotide polymorphism; Steroids; Veterinary colleges; United Kingdom; United Kingdom > UK; Australia; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0259939

Diabetes mellitus (DM) is a common feline endocrinopathy, which is similar to human type 2 diabetes (T2DM) in terms of its pathophysiology. T2DM occurs due to peripheral insulin resistance and/or β-cell dysfunction. Several studies have identified genetic and environmental factors that contribute to susceptibility to human T2DM. In cats, environmental factors such as obesity and physical inactivity have been linked with DM, although to date, the only genetic association that has been demonstrated is with a polymorphism in the feline MC4R gene. The aim of this study was to perform a genome-wide association study (GWAS) to identify polymorphisms associated with feline DM. Illumina Infinium 63k iSelect DNA arrays were used to analyse genomic DNA samples from 200 diabetic domestic shorthair cats and 399 non-diabetic control cats. Data was analysed using PLINK whole genome data analysis toolset. A linear model analysis, EMMAX, was done to test for population structure and HAPLOVIEW was used to identify haplotype blocks surrounding the significant SNPs to assist with candidate gene nomination. A total of 47,497 SNPs were available for analysis. Four SNPs were identified with genome-wide significance: chrA2.4150731 (praw = 9.94 x10-8); chrUn17.115508 (praw = 6.51 x10-8); chrUn17.394136 (praw = 2.53 x10-8); chrUn17.314128 (praw = 2.53 x10-8) as being associated with DM. The first SNP is located within chromosome A2, less than 4kb upstream of the dipeptidyl-peptidase-9 (DPP9) gene, a peptidase involved in incretin inactivation. The remaining three SNPs are located within a haplotype block towards the end of chromosome A3; within this region, genes of interest include TMEM18 and ACP1, both previously associated with T2DM. This study indicates a polygenic component to susceptibility to DM in cats and has highlighted several loci and candidate genes worthy of further investigation.