title: Mouse genome-wide association mapping needs linkage analysis to avoid false-positive Loci.
abstract: We carried out genome-wide association (GWA) studies in inbred mouse strains characterized for their lung tumor susceptibility phenotypes (spontaneous or urethane-induced) with panels of 12,959 (13K) or 138,793 (140K) single-nucleotide polymorphisms (SNPs). Above the statistical thresholds, we detected only SNP rs3681853 on Chromosome 5, two SNPs in the pulmonary adenoma susceptibility 1 (Pas1) locus, and SNP rs4174648 on Chromosome 16 for spontaneous tumor incidence, urethane-induced tumor incidence, and urethane-induced tumor multiplicity, respectively, with the 13K SNP panel, but only the Pas1 locus with the 140K SNP panel. Haplotype analysis carried out in the latter panel detected four additional loci. Loci reported in previous GWA studies failed to replicate. Genome-wide genetic linkage analysis in urethane-treated (BALB/cxC3H/He)F2, (BALB/cxSWR/J)F2, and (A/JxC3H/He)F2 mice showed that Pas1, but none of the other loci detected previously or herein by GWA, had a significant effect. The Lasc1 gene, identified by GWA as a functional element (Nat. Genet., 38:888-95, 2006), showed no genetic effects in the two independent intercross mouse populations containing both alleles, nor was it expressed in mouse normal lung or lung tumors. Our results indicate that GWA studies in mouse inbred strains can suffer a high rate of false-positive results and that such an approach should be used in conjunction with classical linkage mapping in genetic crosses.
authors.affiliation: Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Manenti
authors.forename: Antonella
authors.initials: A
authors.lastname: Galvan
authors.forename: Angela
authors.initials: A
authors.lastname: Pettinicchio
authors.forename: Gaia
authors.initials: G
authors.lastname: Trincucci
authors.forename: Elena
authors.initials: E
authors.lastname: Spada
authors.forename: Anna
authors.initials: A
authors.lastname: Zolin
authors.forename: Silvano
authors.initials: S
authors.lastname: Milani
authors.forename: Anna
authors.initials: A
authors.lastname: Gonzalez-Neira
authors.forename: Tommaso A
authors.initials: TA
authors.lastname: Dragani
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020641:Polymorphism, Single Nucleotide; D014520:Urethane / Q000008:administration & dosage
chemical_list: D002273:Carcinogens; D014520:Urethane