Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci Export

@article{Manenti2009, 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/c×C3H/He)F2, (BALB/c×SWR/J)F2, and (A/J×C3H/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.}, author = {Manenti, Giacomo and Galvan, Antonella and Pettinicchio, Angela and Trincucci, Gaia and Spada, Elena and Zolin, Anna and Milani, Silvano and Gonzalez-Neira, Anna and Dragani, Tommaso A.}, citeulike-article-id = {3885403}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pgen.1000331}, doi = {10.1371/journal.pgen.1000331}, journal = {PLoS Genet}, keywords = {gwas, linkage}, month = {January}, number = {1}, pages = {e1000331+}, posted-at = {2009-01-14 13:11:15}, priority = {3}, publisher = {Public Library of Science}, title = {Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci}, url = {http://dx.doi.org/10.1371/journal.pgen.1000331}, volume = {5}, year = {2009} }

TY - JOUR ID - Manenti2009 L3 - citeulike-article-id:3885403 N2 - 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/c×C3H/He)F2, (BALB/c×SWR/J)F2, and (A/J×C3H/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. IS - 1 JF - PLoS Genet TI - Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci PB - Public Library of Science VL - 5 SP - e1000331 KW - gwas KW - linkage AU - Manenti, Giacomo AU - Galvan, Antonella AU - Pettinicchio, Angela AU - Trincucci, Gaia AU - Spada, Elena AU - Zolin, Anna AU - Milani, Silvano AU - Gonzalez-Neira, Anna AU - Dragani, Tommaso PY - 2009/01// UR - http://dx.doi.org/10.1371/journal.pgen.1000331 ER -