Identification of diabetes susceptibility loci in db mice by combined quantitative trait loci analysis and haplotype mapping.

To identify the disease-susceptibility genes of type 2 diabetes, we performed quantitative trait loci (QTL) analysis in F(2) populations generated from a BKS.Cg-m+/+Lepr(db) and C3H/HeJ intercross, taking advantage of genetically determined obesity and diabetes traits associated with the db gene. A genome-wide scan in the F(2) populations divided by sex and db genotypes identified 14 QTLs in total and 3 major QTLs on chromosome (Chr) 3 (LOD 5.78) for fat pad weight, Chr 15 (LOD 6.64) for body weight, and Chr 16 (LOD 8.15) for blood glucose concentrations. A linear-model-based genome scan using interactive covariates allowed us to consider sex- or sex-by db-specific effects of each locus. For the most significant QTL on Chr 16, the high-resolution haplotype comparison between BKS and C3H strains reduced the critical QTL interval from 20 to 4.6 Mb by excluding shared haplotype regions and identified 11 nonsynonymous single-nucleotide polymorphisms in six candidate genes.

[1]  B. Yandell,et al.  Identification of major quantitative trait loci controlling body weight variation in ob/ob mice. , 2004, Diabetes.

[2]  E. Leiter,et al.  NIDDM Genes in Mice: Deleterious Synergism by Both Parental Genomes Contributes to Diabetogenic Thresholds , 1998, Diabetes.

[3]  K. Imamura,et al.  Genetic analysis of non-insulin-dependent diabetes mellitus in KK and KK-Ay mice. , 1998, European journal of endocrinology.

[4]  Chris S. Haley,et al.  Epistasis: too often neglected in complex trait studies? , 2004, Nature Reviews Genetics.

[5]  K. Hummel,et al.  The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL/KsJ and C57BL/6J strains , 1972, Biochemical Genetics.

[6]  Richard J. Mural,et al.  Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[7]  K P Hummel,et al.  Diabetes, a New Mutafton in the Mouse , 1966, Science.

[8]  Hao Wu,et al.  R/qtl: QTL Mapping in Experimental Crosses , 2003, Bioinform..

[9]  Ross Ihaka,et al.  Gentleman R: R: A language for data analysis and graphics , 1996 .

[10]  H. Kuwano,et al.  Genetic analysis of obese diabetes in the TSOD mouse. , 1999, Diabetes.

[11]  B. Yandell,et al.  Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci. , 2000, Diabetes.

[12]  P. Bork,et al.  The mahogany protein is a receptor involved in suppression of obesity , 1999, Nature.

[13]  G. Churchill,et al.  A statistical framework for quantitative trait mapping. , 2001, Genetics.

[14]  M. Permutt,et al.  Genetic analysis of obesity-induced diabetes associated with a limited capacity to synthesize insulin in C57BL/KS mice: evicence for polygenic control , 1989, Diabetologia.

[15]  James Scott,et al.  Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats , 1999, Nature Genetics.

[16]  J. Friedman,et al.  Molecular mapping of the mouse db mutation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[17]  C. Haley,et al.  A simple regression method for mapping quantitative trait loci in line crosses using flanking markers , 1992, Heredity.

[18]  M. Adams,et al.  A catalog of nonsynonymous polymorphism on mouse Chromosome 16 , 2005, Mammalian Genome.

[19]  Akihiko Konagaya,et al.  TraitMap: an XML-based genetic-map database combining multigenic loci and biomolecular networks , 2004, ISMB/ECCB.

[20]  R. Doerge,et al.  Empirical threshold values for quantitative trait mapping. , 1994, Genetics.

[21]  T. Ogihara,et al.  Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex trait. , 1999, Diabetes.

[22]  Maki Moritani,et al.  Identification of candidate genes in the type 2 diabetes modifier locus using expression QTL. , 2005, Genomics.

[23]  L. Tartaglia,et al.  Evidence That the Diabetes Gene Encodes the Leptin Receptor: Identification of a Mutation in the Leptin Receptor Gene in db/db Mice , 1996, Cell.

[24]  Ron Korstanje,et al.  From QTL to gene: the harvest begins , 2002, Nature Genetics.

[25]  W. Chung,et al.  Genetic modifiers of Leprfa associated with variability in insulin production and susceptibility to NIDDM. , 1997, Genomics.

[26]  D. Coleman.  Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice , 1978, Diabetologia.

[27]  J. Friedman,et al.  Abnormal splicing of the leptin receptor in diabetic mice , 1996, Nature.

[28]  Serge Batalov,et al.  Use of a Dense Single Nucleotide Polymorphism Map for In Silico Mapping in the Mouse , 2004, PLoS biology.

[29]  Tetsuro Toyoda,et al.  Omic space: coordinate-based integration and analysis of genomic phenomic interactions , 2004, Bioinform..

[30]  Janice M. Fullerton,et al.  Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[31]  L. Plum,et al.  Diet-dependent obesity and hypercholesterolemia in the New Zealand obese mouse: identification of a quantitative trait locus for elevated serum cholesterol on the distal mouse chromosome 5. , 2003, Biochemical and biophysical research communications.

[32]  G. Churchill,et al.  Sex- and lineage-specific inheritance of depression-like behavior in the rat , 2004, Mammalian Genome.

[33]  Robert W. Williams,et al.  The nature and identification of quantitative trait loci: a community's view , 2003, Nature Reviews Genetics.