Genetic fine-mapping and identification of candidate genes and variants for adiposity traits in outbred rats

Autor: Keele, Gregory R., Prokop, Jeremy W., He, Hong, Holl, Katie, Littrell, John, Deal, Aaron, Francic, Sanja, Cui, Leilei, Gatti, Daniel M., Broman, Karl W., Tschannen, Michael, Tsaih, Shirng-Wern, Zagloul, Maie, Kim, Yunjung, Baur, Brittany, Fox, Joseph, Robinson, Melanie, Levy, Shawn, Flister, Michael J., Mott, Richard, Valdar, William, Solberg Woods, Leah C
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: Obesity (Silver Spring, Md.)
ISSN: 1930-739X
1930-7381
Popis: Objective Obesity is a major risk factor for multiple diseases and is in part heritable, yet the majority of causative genetic variants that drive excessive adiposity remain unknown. Here, we used outbred heterogeneous stock (HS) rats in controlled environmental conditions to fine-map novel genetic modifiers of adiposity. Methods Body weight and visceral fat pad weights were measured in male HS rats that were also genotyped genome-wide. Quantitative trait loci (QTL) were identified by genome-wide association of imputed single nucleotide polymorphism (SNP) genotypes using a linear mixed effect model that accounts for unequal relatedness between the HS rats. Candidate genes were assessed by protein modeling and mediation analysis of expression for coding and noncoding variants, respectively. Results HS rats exhibited large variation in adiposity traits, which were highly heritable and correlated with metabolic health. Fine-mapping of fat pad weight and body weight revealed three QTL and prioritized five candidate genes. Fat pad weight was associated with missense SNPs in Adcy3 and Prlhr and altered expression of Krtcap3 and Slc30a3, whereas Grid2 was identified as a candidate within the body weight locus. Conclusions These data demonstrate the power of HS rats for identification of known and novel heritable mediators of obesity traits.
Databáze: OpenAIRE
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