Mouse genome-wide association mapping needs linkage analysis to avoid false-positive Loci

Area of Science:

• Genetics
• Oncology
• Bioinformatics

Background:

• Lung tumor susceptibility in mice is a complex trait.
• Genome-wide association (GWA) studies are powerful tools for identifying genetic loci associated with disease phenotypes.
• Previous GWA studies have identified various loci, but replication and validation remain critical.

Purpose of the Study:

• To identify genetic loci associated with spontaneous and urethane-induced lung tumor susceptibility in inbred mouse strains using GWA studies.
• To validate findings from GWA studies using classical genetic linkage analysis.
• To assess the reliability of GWA studies in identifying true genetic associations for complex traits.

Main Methods:

• Genome-wide association studies (GWA) were performed on inbred mouse strains using SNP panels of 13K and 140K.
• Haplotype analysis was conducted on a 140K SNP panel.
• Genome-wide genetic linkage analysis was performed in F2 intercross populations derived from urethane-treated mice.

Main Results:

• GWA studies identified limited significant single nucleotide polymorphisms (SNPs) including rs3681853, SNPs in the pulmonary adenoma susceptibility 1 (Pas1) locus, and rs4174648.
• Haplotype analysis revealed four additional loci.
• Only the Pas1 locus showed a significant effect in linkage analysis; other GWA-identified loci, including the previously reported Lasc1 gene, did not replicate.
• Loci from previous GWA studies failed to replicate in this study.

Conclusions:

• GWA studies in mouse inbred strains can yield a high rate of false-positive results.
• Classical linkage mapping in genetic crosses is essential for validating GWA findings.
• A combined approach of GWA and linkage analysis provides a more robust strategy for dissecting the genetic basis of complex traits like lung tumor susceptibility.