Genetic architecture of adiposity and organ weight using combined generation QTL analysis.

We present here a detailed study of the genetic contributions to adult body size and adiposity in the LG,SM advanced intercross line (AIL), an obesity model. This study represents a first step in fine-mapping obesity quantitative trait loci (QTLs) in an AIL. QTLs for adiposity in this model were previously isolated to chromosomes 1, 6, 7, 8, 9, 12, 13, and 18. This study focuses on heritable contributions and the genetic architecture of fatpad and organ weights. We analyzed both the F(2) and F(3) generations of the LG,SM AIL population single-nucleotide polymorphism (SNP) genotyped with a marker density of approximately 4 cM. We replicate 88% of the previously identified obesity QTLs and identify 13 new obesity QTLs. Nearly half of the single-trait QTLs were sex-specific. Several broad QTL regions were resolved into multiple, narrower peaks. The 113 single-trait QTLs for organs and body weight clustered into 27 pleiotropic loci. A large number of epistatic interactions are described which begin to elucidate potential interacting molecular networks. We present a relatively rapid means to obtain fine-mapping details from AILs using dense marker maps and consecutive generations. Analysis of the complex genetic architecture underlying fatpad and organ weights in this model may eventually help to elucidate not only heritable contributions to obesity but also common gene sets for obesity and its comorbidities.