Identification of Candidate Genes and Pathways Associated with Obesity-Related Traits in Canines via Gene-Set Enrichment and Pathway-Based GWAS Analysis

SIMPLE SUMMARY: Obesity is a serious health issue and is increasing at an alarming rate in several dog breeds, but there is limited information on the genetic mechanism underlying it. Moreover, there have been very few reports on genetic markers associated with canine obesity. These studies were limited to the use of a single breed in the association study. In this study, we have performed a GWAS and supplemented it with gene-set enrichment and pathway-based analyses to identify causative loci and genes associated with canine obesity in 18 different dog breeds. From the GWAS, the significant markers associated with obesity-related traits including body weight (CACNA1B, C22orf39, U6, MYH14, PTPN2, SEH1L) and blood sugar (PRSS55, GRIK2), were identified. Furthermore, the gene-set enrichment and pathway-based analysis (GESA) highlighted five enriched pathways (Wnt signaling pathway, adherens junction, pathways in cancer, axon guidance, and insulin secretion) and seven GO terms (fat cell differentiation, calcium ion binding, cytoplasm, nucleus, phospholipid transport, central nervous system development, and cell surface) which were found to be shared among all the traits. ABSTRACT: The present study aimed to identify causative loci and genes enriched in pathways associated with canine obesity using a genome-wide association study (GWAS). The GWAS was first performed to identify candidate single-nucleotide polymorphisms (SNPs) associated with obesity and obesity-related traits including body weight and blood sugar in 18 different breeds of 153 dogs. A total of 10 and 2 SNPs were found to be significantly (p < 3.74 × 10(−7)) associated with body weight and blood sugar, respectively. None of the SNPs were identified to be significantly associated with obesity trait. We subsequently followed up the GWAS analysis with gene-set enrichment and pathway analyses. A gene-set with 1057, 1409, and 1243 SNPs annotated to 449, 933 and 820 genes for obesity, body weight, and blood sugar, respectively was created by sub-setting the GWAS result at a threshold of p < 0.01 for the gene-set enrichment analysis. In total, 84 GO and 21 KEGG pathways for obesity, 114 GO and 44 KEGG pathways for blood sugar, 120 GO and 24 KEGG pathways for body weight were found to be enriched. Among the pathways and GO terms, we highlighted five enriched pathways (Wnt signaling pathway, adherens junction, pathways in cancer, axon guidance, and insulin secretion) and seven GO terms (fat cell differentiation, calcium ion binding, cytoplasm, nucleus, phospholipid transport, central nervous system development, and cell surface) that were found to be shared among all the traits. Our data provide insights into the genes and pathways associated with obesity and obesity-related traits.