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

Giacomo Manenti, Antonella Galvan, Angela Pettinicchio, Gaia Trincucci, Elena Spada, Anna Zolin, Silvano Milani, Anna Gonzalez-Neira, Tommaso A. Dragani

Research output: Contribution to journalArticle

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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 urethanetreated (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.

Original languageEnglish
Article numbere1000331
JournalPLoS Genetics
Volume5
Issue number1
DOIs
Publication statusPublished - Jan 2009

Fingerprint

Chromosome Mapping
single nucleotide polymorphism
chromosome mapping
Single Nucleotide Polymorphism
linkage (genetics)
polymorphism
tumor
genome
Genome
urethane
Lung
loci
adenoma
Genome-Wide Association Study
Urethane
mice
lungs
Adenoma
Inbred Strains Mice
lung neoplasms

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Mouse genome-wide association mapping needs linkage analysis to avoid false-positive loci. / Manenti, Giacomo; Galvan, Antonella; Pettinicchio, Angela; Trincucci, Gaia; Spada, Elena; Zolin, Anna; Milani, Silvano; Gonzalez-Neira, Anna; Dragani, Tommaso A.

In: PLoS Genetics, Vol. 5, No. 1, e1000331, 01.2009.

Research output: Contribution to journalArticle

Manenti, G, Galvan, A, Pettinicchio, A, Trincucci, G, Spada, E, Zolin, A, Milani, S, Gonzalez-Neira, A & Dragani, TA 2009, 'Mouse genome-wide association mapping needs linkage analysis to avoid false-positive loci', PLoS Genetics, vol. 5, no. 1, e1000331. https://doi.org/10.1371/journal.pgen.1000331
Manenti, Giacomo ; Galvan, Antonella ; Pettinicchio, Angela ; Trincucci, Gaia ; Spada, Elena ; Zolin, Anna ; Milani, Silvano ; Gonzalez-Neira, Anna ; Dragani, Tommaso A. / Mouse genome-wide association mapping needs linkage analysis to avoid false-positive loci. In: PLoS Genetics. 2009 ; Vol. 5, No. 1.
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