Use of a Dense Single Nucleotide Polymorphism Map for In Silico Mapping in the MouseRapid expansion of available data, both phenotypic and genotypic, for multiple strains of mice has enabled the development of new methods to interrogate the mouse genome for functional genetic perturbations. In silico mapping provides an expedient way to associate the natural diversity of phenotypic traits with ancestrally inherited polymorphisms for the purpose of dissecting genetic traits. In mouse, the current single nucleotide polymorphism (SNP) data have lacked the density across the genome and coverage of enough strains to properly achieve this goal. To remedy this, 470,407 allele calls were produced for 10,990 evenly spaced SNP loci across 48 inbred mouse strains. Use of the SNP set with statistical models that considered unique patterns within blocks of three SNPs as an inferred haplotype could successfully map known single gene traits and a cloned quantitative trait gene. Application of this method to high-density lipoprotein and gallstone phenotypes reproduced previously characterized quantitative trait loci (QTL). The inferred haplotype data also facilitates the refinement of QTL regions such that candidate genes can be more easily identified and characterized as shown for adenylate cyclase 7.
Genome-Wide Haplotype Association Mapping in Mice Identifies a Genetic Variant in <i>CER1</i> Associated With BMD and Fracture in Southern Chinese WomenPaul L. F. Tang, Ching‐Lung Cheung, Pak C. Sham et al.|Journal of Bone and Mineral Research|2008 BMD is a heritable trait and risk indicator for osteoporosis. In this study, we used a genome-wide haplotype association mapping (HAM) approach to identify a haplotype block within Cer1 that partitions inbred mice strains into high and low BMD groups. A cohort of 1083 high and low BMD human subjects were studied, and a nonsynonymous SNP (rs3747532) in human CER1 was identified to be associated with increased risk of both low BMD in premenopausal women (OR: 2.2; 95% CI: 1.0-4.6; p < 0.05) and increased risk of vertebral fractures (OR: 1.82, p = 0.025) in the postmenopausal cohort. We also showed that Cer1 is expressed in mouse bone and growth plate by RT-PCR, immunohistochemistry, and in situ hybridization, consistent with polymorphisms potentially influencing BMD. Our successful identification of an association with CER1 in humans together with our mouse study suggests that CER1 may play a role in the development of bone or its metabolism. Our study highlights the use of publicly available databases for rapidly surveying the genome for quantitative trait loci.