High-Density Genotypes of Inbred Mouse Strains: Improved Power and Precision of Association Mapping

Abstract

Human genome-wide association studies have identified thousands of loci associated with disease phenotypes. Genome-wide association studies also have become feasible using rodent models and these have some important advantages over human studies, including controlled environment, access to tissues for molecular profiling, reproducible genotypes, and a wide array of techniques for experimental validation. Association mapping with common mouse inbred strains generally requires 100 or more strains to achieve sufficient power and mapping resolution; in contrast, sample sizes for human studies typically are one or more orders of magnitude greater than this. To enable well-powered studies in mice, we have generated high-density genotypes for ∼175 inbred strains of mice using the Mouse Diversity Array. These new data increase marker density by 1.9-fold, have reduced missing data rates, and provide more accurate identification of heterozygous regions compared with previous genotype data. We report the discovery of new loci from previously reported association mapping studies using the new genotype data. The data are freely available for download, and Web-based tools provide easy access for association mapping and viewing of the underlying intensity data for individual loci.

Keywords: HMDP; genotyping; mouse; mouse diversity array.

Figure 1

Comparisons of Prior genotypes with Mouse Diversity Array (MDA) genotypes. (A) Fraction of single-nucleotide polymorphisms (SNPs) with missing calls in each strain for Prior (left) and MDA (right) genotypes. The red line indicates the average value. (B) Histogram showing the proportion of missing strains for each SNP for the prior (left) and MDA (right) genotypes. Highlighted in yellow and displayed as a percentage are the numbers of SNPs with more than 10% missing values (7% for prior, 0.03% for MDA). (C) Fraction of heterozygous SNPs within each strain for prior (left) and MDA (right) genotypes. The red line indicates the average value. (D) Histogram of concordance between SNPs found in both genotyping sets.

Figure 2

Allele frequencies in genotyping datasets. Histograms of the allele frequency of single-nucleotide polymorphisms (SNPs) in the Prior (left) and Mouse Diversity Array (right) genotypes. Highlighted in yellow and displayed as a percentage are the SNPs whose allele frequencies are too low for genome-wide association studies.

Figure 3

Effects of new single-nucleotide polymorphisms (SNPs) on genome-wide association study results. In both cases, the phenotype being used is total heart weight after isoproterenol treatment. Red line indicates genome-wide significance threshold (4.1E-6). (A) Results using EMMA on the Prior genotypes reveals a single locus on chromosome 1. (B) Results using EMMA on Mouse Diversity Array (MDA) genotypes reveals four additional loci. (C) Results using EMMA on the MDA genotypes using a kinship matrix generated from the Prior genotypes does not demonstrably change the results from B).