Faculty Collaboration Database

Genetic Fine-Mapping and Identification of Candidate Genes and Variants for Adiposity Traits in Outbred Rats. Obesity (Silver Spring) 2018 Jan;26(1):213-222

Date

12/02/2017

Pubmed ID

29193816

Pubmed Central ID

PMC5740008

DOI

10.1002/oby.22075

Scopus ID

2-s2.0-85036513924 (requires institutional sign-in at Scopus site)   47 Citations

Abstract

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, outbred heterogeneous stock (HS) rats were used 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.

Author List

Keele GR, Prokop JW, He H, Holl K, Littrell J, Deal A, Francic S, Cui L, Gatti DM, Broman KW, Tschannen M, Tsaih SW, Zagloul M, Kim Y, Baur B, Fox J, Robinson M, Levy S, Flister MJ, Mott R, Valdar W, Solberg Woods LC

Author

Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adiposity
Animals
Body Weight
Chromosome Mapping
Genetic Variation
Genome-Wide Association Study
Genotype
Male
Obesity
Phenotype
Polymorphism, Single Nucleotide
Rats