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.
Moritani
Maki
M
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan.
Togawa
Katsuhiko
K
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan; First Institute of New Drug Discovery, Otsuka Pharmaceutical, Inc., Tokushima 771-0192, Japan.
Yaguchi
Hiroshi
H
Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc., Naruto 772-8601, Japan.
Fujita
Yuka
Y
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan.
Yamaguchi
Yuka
Y
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan.
Inoue
Hiroshi
H
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan.
Kamatani
Naoyuki
N
Division of Statistical Genetics, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
Itakura
Mitsuo
M
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan. Electronic address: itakura@genome.tokushima-u.ac.jp.
D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D006239:Haplotypes / Q000235:genetics*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*