Companion animals

Integration of GWAS, Long and Short Reads Sequencing to Identify Genetic Variants Associated with Hypertrophic Cardiomyopathy in Cats

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Abstract

Hypertrophic cardiomyopathy (HCM) is the most common heritable heart disease in both cats and humans, affecting approximately 0.2% of the human and up to 15% of cats. It is characterised by primary left-ventricular myocardial hypertrophy and is associated with an increased risk of aortic thromboembolism in cats and heart failure with significant morbidity and mortality in both species. Despite its high prevalence, disease-modifying treatments remain unavailable, highlighting the need to better understand the genetic and molecular mechanisms underlying HCM susceptibility. While over 1,500 causative variants have been identified in human, predominantly affecting sarcomeric genes, only five feline HCM-associated variants have been reported to date, largely reflecting the limited scale of feline genomic studies. Genome-wide association studies (GWAS) were performed using the Illumina Feline 63K SNP array in a multi-breed cohort of cats, including British Shorthair (BSH), Birman, Sphynx, Bengal, and Domestic Shorthair (DSH) populations. Analyses were conducted using the GEMMA algorithm with age, sex, and breed included as covariates, identifying thirty-five candidate loci associated with HCM. To further investigate these regions, whole-genome sequencing (WGS) was performed in 53 cats (29 HCM cases and 24 healthy elderly controls) representing the same five breeds. To complement short-read sequencing, a subset of eight cats (BSH, n = 4; Bengal, n = 4) was sequenced at approximately 40à— coverage using Oxford Nanopore Technologies (ONT) long-read sequencing. WGS achieved an average depth of ~30à— per sample. Reads were aligned to the FelCat9.0 using BWA-MEM, and variants were called and filtered following GATK Best Practices. Within candidate loci, allelic and genotypic frequencies were compared between HCM and controls using Chi-square (χ²) tests. In DSH, over 105,000 variants (P < 0.05) spanning 84 genes were identified, including 22 high-impact and 323 missense variants, several of which were more frequent in HCM and implicated in cardiac structural and signalling pathways. In the BSH, 1,612 variants (padj < 0.05) overlapping 44 genes were detected, the majority residing in intronic regions.1 missense and 1 frameshift variant were identified based on the most severe predicted consequences, with variants frequently located near genes involved in cardiac development and cellular signalling. Analyses for the remaining breeds are ongoing. For ONT data, structural variants (SVs) were detected using Sniffles2 and single-nucleotide variants using bcftools for PLINK-based analyses. As a preliminary analysis, SVs were prioritised based on size (≥1 kb) and differences in carrier counts between HCM cases and controls within each breed. This approach identified 2,741 SVs in BSH and 3,820 SVs in Bengal cats, with case-enriched exonic SVs mapping to 83 and 591 genes, respectively. Exploratory functional enrichment analyses highlighted pathways related to cardiac development and function, ion transport and cellular signalling. Collectively, these findings support a complex, polygenic architecture of feline HCM.

Keywords: 2026

How to Cite:

Sidekli, O., Smedley, T., Raffle, J., Crean, A., Hinsu, A., Fuentes, V., Connolly, D. & Psifidi, A., (2026) “Integration of GWAS, Long and Short Reads Sequencing to Identify Genetic Variants Associated with Hypertrophic Cardiomyopathy in Cats”, World Congress on Genetics Applied to Livestock Production Digital Archive 2026(1): 2287057. doi: https://doi.org/10.31274/wcgalp.24202

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