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

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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.

Vyšlo v časopise: Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci. PLoS Genet 5(1): e32767. doi:10.1371/journal.pgen.1000331
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000331

Souhrn

Zdroje

1. ChapmanNH

ThompsonEA

2001 Linkage disequilibrium mapping: the role of population history, size, and structure. Adv Genet 42 413 437

2. AbecasisGR

GhoshD

NicholsTE

2005 Linkage disequilibrium: ancient history drives the new genetics. Hum Hered 59 118 124

3. ManentiG

StaffordA

De GregorioL

GariboldiM

FalvellaFS

1999 Linkage disequilibrium and physical mapping of Pas1 in mice. Genome Res 9 639 646

4. ManentiG

GalbiatiF

Giannì-BarreraR

PettinicchioA

AcevedoA

2004 Haplotype sharing suggests that a genomic segment containing six genes accounts for the pulmonary adenoma susceptibility 1 (Pas1) locus activity in mice. Oncogene 23 4495 4504

5. ManentiG

DraganiTA

2005 Pas1 haplotype-dependent genetic predisposition to lung tumorigenesis in rodents: a meta-analysis. Carcinogenesis 26 875 882

6. GrupeA

GermerS

UsukaJ

AudD

BelknapJK

2001 In silico mapping of complex disease-related traits in mice. Science 292 1915 1918

7. WangD

YouM

2005 Five loci, SLT1 to SLT5, controlling the susceptibility to spontaneously occurring lung cancer in mice. Cancer Res 65 8158 8165

8. LiuP

WangY

VikisH

MaciagA

WangD

2006 Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred mice. Nat Genet 38 888 895

9. FenskeTS

McMahonC

EdwinD

JarvisJC

CheverudJM

2006 Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice. Cancer Res 66 5029 5038

10. DevereuxTR

WisemanRW

KaplanN

GarrenS

FoleyJF

1994 Assignment of a locus for mouse lung tumor susceptibility to proximal chromosome 19. Mamm Genome 5 749 755

11. ManentiG

GariboldiM

FiorinoA

ZeddaAI

PierottiMA

1997 Pas1 is a common lung cancer susceptibility locus in three mouse strains. Mamm Genome 8 801 809

12. ManentiG

GariboldiM

FiorinoA

ZanesiN

PierottiMA

1997 Genetic mapping of lung cancer modifier loci specifically affecting tumor initiation and progression. Cancer Res 57 4164 4166

13. GariboldiM

ManentiG

CanzianF

FalvellaFS

RadiceMT

1993 A major susceptibility locus to murine lung carcinogenesis maps on chromosome 6. Nature Genet 3 132 136

14. WadeCM

KulbokasEJIII

KirbyAW

ZodyMC

MullikinJC

2002 The mosaic structure of variation in the laboratory mouse genome. Nature 420 574 578

15. FrazerKA

WadeCM

HindsDA

PatilN

CoxDR

2004 Segmental phylogenetic relationships of inbred mouse strains revealed by fine-scale analysis of sequence variation across 4.6 mb of mouse genome. Genome Res 14 1493 1500

16. YangH

BellTA

ChurchillGA

Pardo-Manueld

2007 On the subspecific origin of the laboratory mouse. Nat Genet 39 1100 1107

17. CervinoAC

DarvasiA

FallahiM

MaderCC

TsinoremasNF

2007 An integrated in silico gene mapping strategy in inbred mice. Genetics 175 321 333

18. VielandVJ

2001 The replication requirement. Nat Genet 29 244 245

19. LeeGH

NishimoriH

SasakiY

MatsushitaH

KitagawaT

2003 Analysis of lung tumorigenesis in chimeric mice indicates the Pulmonary adenoma resistance 2 (Par2) locus to operate in the tumor-initiation stage in a cell-autonomous manner: detection of polymorphisms in the Poli gene as a candidate for Par2. Oncogene 22 2374 2382

20. DarvasiA

2001 In silico mapping of mouse quantitative trait loci. Science 294 2423

21. PayseurBA

PlaceM

2007 Prospects for association mapping in classical inbred mouse strains. Genetics 175 1999 2008

22. MalkinsonAM

1989 The genetic basis of susceptibility to lung tumors in mice. Toxicology 54 241 271

23. ToMD

Perez-LosadaJ

MaoJH

HsuJ

JacksT

2006 A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice. Nat Genet 38 926 930

24. ShenR

FanJB

CampbellD

ChangW

ChenJ

2005 High-throughput SNP genotyping on universal bead arrays. Mutat Res 573 70 82

25. ZaykinDV

WestfallPH

YoungSS

KarnoubMA

WagnerMJ

2002 Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 53 79 91

26. SimonRM

KornEL

McShaneLM

RadmacherMD

WrightGM

2004 Design and analysis of DNA microarray investigations New York Springer-Verlag 80

27. BromanKW

WuH

SenS

ChurchillGA

2003 R/qtl: QTL mapping in experimental crosses. Bioinformatics 19 889 890

28. LincolnSE