Genetic Fine‐mapping and Gene Identification of Adiposity Traits in Outbred Rats

Obesity and overweight are major risk factors for multiple diseases including cardiovascular disease and type 2 diabetes. Genetic factors are known to contribute significantly to obesity and related traits with heritability ranging from 50‐80%. Human genome‐wide association studies have identified over 50 genes for traits related to adiposity. These genes, however, explain less than 10% of the heritable variance. Heterogeneous stock (HS) rats are outbred from eight inbred strains and allow genetic fine‐mapping to only a few Megabases. The goal of the current study was to use HS rats to fine‐map adiposity traits genome‐wide and identify underlying candidate genes. We measured body weight, body mass index and visceral adiposity in 1090 male HS rats and genotyped all rats using the Affymetrix 10K SNP array. Linkage disequilibrium mapping by mixed model regression was used to identify significant loci. We identified one or more significant loci for all traits, with an average confidence interval of only 2.2 Mb. Using expression data and founder sequence, we identified potential candidate genes within several loci, including those that have previously been identified in human genome‐wide association studies. Protein modeling was used to support a causal role for some of the genes. These results demonstrate the power of HS rats for fine‐mapping metabolic traits and rapidly identifying candidate genes.Supported by NIH R01 DK‐088975 and the Individualized Medicine Institute at MCW.