Integrating QTL and high-density SNP analyses in mice to identify Insig2 as a susceptibility gene for plasma cholesterol levels

Cervino, Alessandra; Li, Guoya; Edwards, Stephen W.; Zhu, Jun; Laurie, Cathy C.; Tokiwa, George; Lum, Pek Yee; Wang, Susanna; Castellini, Lawrence W.; Lusis, Aldons J.; Carlson, Sonia; Sachs, Alan B.; Schadt, Eric E.

doi:10.1016/j.ygeno.2005.07.010

Cited by 124 publications

(126 citation statements)

References 42 publications

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“…SNP genotype data were collected primarily from three sources: GNF (Wiltshire et al 2003), Rosetta/ Merck (Cervino et al 2005), and the Broad Institute (http://www.broad.mit.edu/$mjdaly/mousehapmap). All SNP locations were mapped to NCBIM33.…”

Section: Methodsmentioning

confidence: 99%

“…For example, several research groups have investigated the use of a panel of diverse inbred strains of mice (Bogue and Grubb 2004) (collectively referred to here as the mouse diversity panel, MDP) for these QTL mapping studies (Grupe et al 2001;Liao et al 2004;Pletcher et al 2004;Cervino et al 2005). In contrast to mapping populations derived from controlled crosses, the strains of the MDP have been derived over the past century of semistructured breeding and inbreeding (Beck et al 2000).…”

Section: T He Use Of Modern Genetics In Model Organismsmentioning

confidence: 99%

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Genomewide Association Analysis in Diverse Inbred Mice: Power and Population Structure

McClurg

Janes

et al. 2007

Genetics

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The discovery of quantitative trait loci (QTL) in model organisms has relied heavily on the ability to perform controlled breeding to generate genotypic and phenotypic diversity. Recently, we and others have demonstrated the use of an existing set of diverse inbred mice (referred to here as the mouse diversity panel, MDP) as a QTL mapping population. The use of the MDP population has many advantages relative to traditional F 2 mapping populations, including increased phenotypic diversity, a higher recombination frequency, and the ability to collect genotype and phenotype data in community databases. However, these methods are complicated by population structure inherent in the MDP and the lack of an analytical framework to assess statistical power. To address these issues, we measured gene expression levels in hypothalamus across the MDP. We then mapped these phenotypes as quantitative traits with our association algorithm, resulting in a large set of expression QTL (eQTL). We utilized these eQTL, and specifically cis-eQTL, to develop a novel nonparametric method for association analysis in structured populations like the MDP. These eQTL data confirmed that the MDP is a suitable mapping population for QTL discovery and that eQTL results can serve as a gold standard for relative measures of statistical power.

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Section: Methodsmentioning

confidence: 99%

Section: T He Use Of Modern Genetics In Model Organismsmentioning

confidence: 99%

Genomewide Association Analysis in Diverse Inbred Mice: Power and Population Structure

McClurg

Janes

et al. 2007

Genetics

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“…As a result, associating breedspecific genotypes with ''fixed'' phenotypes in multiple breeds (across-breed mapping) presents a powerful tool for identifying quantitative trait loci (QTL) that may form the genetic basis for the phenotypic diversity observed in dog breeds. Similar approaches have been described using inbred mouse strains (Grupe et al 2001;Liao et al 2004;Pletcher et al 2004;Wang et al 2005), and these have 1 been combined with classical QTL analysis (Park et al 2003;Dipetrillo et al 2004;Wang et al 2004;Cervino et al 2005). However, the number of inbred mouse lines available are far fewer than the number of dog breeds, and the number of phenotypes offered by mice much fewer than what is offered by the nearly 300 breeds of domestic dog.…”

mentioning

confidence: 94%

Single-Nucleotide-Polymorphism-Based Association Mapping of Dog Stereotypes

Jones¹,

Chase

Martin³

et al. 2008

Genetics

143

168

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Phenotypic stereotypes are traits, often polygenic, that have been stringently selected to conform to specific criteria. In dogs, Canis familiaris, stereotypes result from breed standards set for conformation, performance (behaviors), etc. As a consequence, phenotypic values measured on a few individuals are representative of the breed stereotype. We used DNA samples isolated from 148 dog breeds to associate SNP markers with breed stereotypes. Using size as a trait to test the method, we identified six significant quantitative trait loci (QTL) on five chromosomes that include candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Less well-documented data for behavioral stereotypes tentatively identified loci for herding, pointing, boldness, and trainability. Four significant loci were identified for longevity, a breed characteristic not under direct selection, but inversely correlated with breed size. The strengths and limitations of the approach are discussed as well as its potential to identify loci regulating the within-breed incidence of specific polygenic diseases.

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“…However, as demonstrated recently, the increasing availability of high-density single-nucleotide polymorphism (SNP) maps of mice and consecutive in silico QTL mapping approaches may ultimately lead to the identification of susceptibility genes for complex traits. [6][7][8] As a systematic approach is necessary to identify candidate regions for such further analysis, we have performed a meta-analysis on 34 independent genome-wide scans in mice for obesity-related traits using the truncated product method. 9 Our analysis of 162 non-redundant QTL for body weight and 117 QTL for fat weight and body fat percentage reveals several major regions on chromosomes 1, 2, 7, 11, 15, and 17 that appear to be involved in the control of body weight and adiposity.…”

Section: Introductionmentioning

confidence: 99%

A meta-analysis of quantitative trait loci associated with body weight and adiposity in mice

et al. 2006

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Objective: Cross-breeding experiments with different mouse strains have successfully been used by many groups to identify genetic loci that predispose for obesity. In order to provide a statistical assessment of these quantitative trait loci (QTL) as a basis for a systematic investigation of candidate genes, we have performed a meta-analysis of genome-wide linkage scans for body weight and body fat. Data: From a total of 34 published mouse cross-breeding experiments, we compiled a list of 162 non-redundant QTL for body weight and 117 QTL for fat weight and body fat percentage. Collectively, these studies include data from 42 different parental mouse strains and 414 500 individual mice. Methods: The results of the studies were analyzed using the truncated product method (TPM). Results: The analysis revealed significant evidence (logarithm of odds (LOD) score 44.3) for linkage of body weight and adiposity to 49 different segments of the mouse genome. The most prominent regions with linkage for body weight and body fat (LOD scores 14.8-21.8) on chromosomes 1, 2, 7, 11, 15, and 17 contain a total of 58 QTL for body weight and body fat. At least 34 candidate genes and genetic loci, which have been implicated in regulation of body weight and body composition in rodents and/or humans, are found in these regions, including CCAAT/enhancer-binding protein alpha (C/EBPA), sterol regulatory element-binding transcription factor 1 (SREBP-1), peroxisome proliferator activator receptor delta (PPARD), and hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1). Our results demonstrate the presence of numerous distinct consensus QTL regions with highly significant LOD scores that control body weight and body composition. An interactive physical map of the QTL is available online at

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Integrating QTL and high-density SNP analyses in mice to identify Insig2 as a susceptibility gene for plasma cholesterol levels

Cited by 124 publications

References 42 publications

Genomewide Association Analysis in Diverse Inbred Mice: Power and Population Structure

Genomewide Association Analysis in Diverse Inbred Mice: Power and Population Structure

Single-Nucleotide-Polymorphism-Based Association Mapping of Dog Stereotypes

A meta-analysis of quantitative trait loci associated with body weight and adiposity in mice

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