Genome wide association study in 3,173 outbred rats identifies multiple loci for body weight, adiposity, and fasting glucose

Abstract

Obesity is a global health crisis that is influenced by both genetic and environmental factors.Rodent model organisms can be used to understand the biological and genetic basis of obesity and related morphological traits. A major advantage of model organisms is that they can be studied under uniform environmental conditions, thus reducing the complex role of environment and gene by environment interactions. Furthermore, fat pads and other tissues can be dissected and weighed, so that their role in determining body weight can be precisely defined. Highly recombinant populations allow for genetic fine-mapping of complex traits, greatly reducing the number of plausible candidate genes. We performed the largest rat GWAS ever undertaken, using 3,173 male and female adult N/NIH heterogeneous stock (HS) rats, which were created by mixing 8 inbred strains. We identified 31 independent loci for body weight, body length, body mass index, fat pad weight (retroperitoneal, epididymal, and parametrial), and fasting glucose.We observed strong evidence of pleotropic effects across multiple phenotypes. Three loci contained only a single gene (Epha5, Nrg1 and Klhl14), whereas others were larger and contained many genes. We replicated a locus containing Prlhr, and a second locus containing Adcy3, which we had previously identified in a smaller HS rat study. Finally, by subsampling our dataset, we showed an exponential growth of significant loci as sample size increased towards 3,173. Our results demonstrate the potential for rodent studies to add to our understanding of the molecular genetic factors that contribute to obesity-relevant traits and emphasize the importance of sample size.

Genetic mapping of multiple metabolic traits identifies novel genes for adiposity, lipids and insulin secretory capacity in outbred rats

“…Here, we use the HS rat model to dissect the genetic architecture of metabolic and adiposityrelated phenotypes. This work significantly extends our previous study [10,11] in which we mapped physiological QTLs (pQTL) for adiposity traits. First, we use many more animals, assess additional metabolic traits and measure gene expression in two metabolically active tissues.…”

“…Animal models of obesity have several advantages over human studies; environmental and dietary factors are controllable, and -omic data such as transcriptomics can be collected from relevant tissues under controlled conditions. In particular, the heterogeneous stock (HS) rats are an established model for the genetic study of obesity [10,11]. The HS are descended from eight fully sequenced inbred founder strains [12,13].…”

Incentive salience attribution, “sensation-seeking” and “novelty-seeking” are independent traits in a large sample of male and female heterogeneous stock rats

“…The current study represents the first to investigate the relationship between addiction susceptibility traits using such a large sample size. We were fortunate to exploit a large sample of a uniquely heterogeneous rat population that is concurrently being used for other investigations that require such sample sizes 46 . The reported findings uncover novel relationships between multiple measures of incentive salience attribution, led to a new metric that captures "incentive value", and revealed sex differences that were not previously apparent.…”

Adapting Genotyping-by-Sequencing and Variant Calling for Heterogeneous Stock Rats

“…Tissue samples and DNA extraction Samples for this study originated from three sources: an in-house advanced intercross line (AIL) derived from LG/J and SM/J mice (Gonzales et al 2018), Sprague Dawley (SD) rats from Charles River Laboratories and Harlan Sprague Dawley, Inc. (Gileta et al 2018), and an HS rat colony (Woods and Mott 2017;Chitre et al 2018). Early stages of ddGBS optimization utilized AIL genomic DNA extracted from spleen by a standard salting-out protocol.…”