ObjectiveObesity 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.MethodsBody 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.ResultsHS 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.ConclusionsThese data demonstrate the power of HS rats for identification of known and novel heritable mediators of obesity traits.

Objective Obesity is influenced by genetic and environmental factors. Despite the success of human genome‐wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits. Methods This study measured obesity‐relevant traits, including body weight, body length, BMI, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat genome‐wide association study to date. Genetic loci were identified using a linear mixed model to account for the complex family relationships of the HS and using covariates to account for differences among the three phenotyping centers. Results This study identified 32 independent loci, several of which contained only a single gene (e.g., Epha5, Nrg1, Klhl14) or obvious candidate genes (e.g., Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity‐related traits, and there was extensive pleiotropy at individual loci. Conclusions This study demonstrates the utility of HS rats for investigating the genetics of obesity‐related traits across institutions and identify several candidate genes for future functional testing.

Solberg Woods LC, Holl K, Tschannen M, Valdar W. Finemapping a locus for glucose tolerance using heterogeneous stock rats. Physiol Genomics 41: 102-108, 2010. First published January 12, 2010 doi:10.1152/physiolgenomics.00178.2009.-Heterogeneous stock (HS) animals provide the ability to map quantitative trait loci at high resolution [Ͻ5 Megabase (Mb)] in a relatively short time period. In the current study, we hypothesized that the HS rat colony would be useful for fine-mapping a region on rat chromosome 1 that has previously been implicated in glucose regulation. We administered a glucose tolerance test to 515 HS rats and genotyped these animals with 69 microsatellite markers, spaced an average distance of Ͻ1 Mb apart, on a 67 Mb region of rat chromosome 1. Using regression modeling of inferred haplotypes based on a hidden Markov model reconstruction and mixed model analysis in which we accounted for the complex family structure of the HS, we identified one sharp peak within this region. Using positional bootstrapping, we determined the most likely location of this locus is from 205.04 to 207.48 Mb. This work demonstrates the utility of HS rats for finemapping complex traits and emphasizes the importance of taking into account family structure when using highly recombinant populations.type 2 diabetes; quantitative trait loci; mapping; mixed model analysis HETEROGENEOUS STOCKS (HS) are a powerful tool for rapidly fine-mapping loci involved in complex traits (41). These animals are originally derived from eight inbred founder strains and then bred for 40 -50 generations in a pattern that aims to minimize inbreeding (1, 16). The resulting colony represents a random mosaic of the founders, with the distance between recombination approaching 2 cM, enabling rapid fine-mapping of quantitative trait loci (QTLs) (31). An HS rat stock was developed in 1984 using the following eight inbred founder strains: ACI/N, BN/N, BUF/N, F344/N, M520/N, MR/N, WKY/N, WN/N (16). Multiple phenotypes have been finemapped using the HS mouse (41). To date, however, the HS rat colony has only been used to fine-map a single locus for fear-related behavior (18).We hypothesized that HS rats would be useful for finemapping a region on rat chromosome 1 that has previously been identified for several metabolic traits, including glucose tolerance, in several linkage studies in the rat (3,11,12,20,32,37,45,46). Human linkage and genome-wide association studies for type 2 diabetes have also identified the homologous human region (6,19,25). While many of the previous rat studies have used animal models of diabetes such as the Goto-Kakizaki (GK) or Otsuka Long-Evans Tokushima Fatty rat (11,12,20,32,46), this locus has also been mapped for diabetes or glucose tolerance using founders of the HS colony: Wistar Kyoto (WKY) and August Copenhagen Irish (ACI) (37,45). These studies indicate that diabetes susceptibility alleles will segregate within the HS rat colony. While the WKY rat has previously been found to exhibit hyperglycemia and glucose intoleranc...

There are a number of traits that are thought to increase susceptibility to addiction, and some of these are modeled in preclinical studies. For example, “sensation-seeking” is predictive of the initial propensity to take drugs; whereas “novelty-seeking” predicts compulsive drug-seeking behavior. In addition, the propensity to attribute incentive salience to reward cues can predict the propensity to approach drug cues, and reinstatement or relapse, even after relatively brief periods of drug exposure. The question addressed here is the extent to which these three ‘vulnerability factors’ are related; that is, predictive of one another. Some relationships have been reported in small samples, but here a large sample of 1,598 outbred male and female heterogeneous stock rats were screened for Pavlovian conditioned approach behavior (to obtain an index of incentive salience attribution; ‘sign-tracking’), and subsequently tested for sensation-seeking and novelty-seeking. Despite the large N there were no significant correlations between these traits, in either males or females. There were, however, novel relationships between multiple measures of incentive salience attribution and, based on these findings, we generated a new metric that captures “incentive value”. Furthermore, there were sex differences on measures of incentive salience attribution and sensation-seeking behavior that were not previously apparent.