Power of a genome scan to detect and locate quantitative trait loci in cattle using dense single nucleotide polymorphisms.

There is increasing use of dense single nucleotide polymorphisms (SNPs) for whole-genome association studies (WGAS) in livestock to map and identify quantitative trait loci (QTL). These studies rely on linkage disequilibrium (LD) to detect an association between SNP genotypes and phenotypes. The power and precision of these WGAS are unknown, and will depend on the extent of LD in the experimental population. One complication for WGAS in livestock populations is that they typically consist of many paternal half-sib families, and in some cases full-sib families; unless this subtle population stratification is accounted for, many spurious associations may be reported. Our aim was to investigate the power, precision and false discovery rates of WGAS for QTL discovery, with a commercial SNP array, given existing patterns of LD in cattle. We also tested the efficiency of selective genotyping animals. A total of 365 cattle were genotyped for 9232 SNPs. We simulated a QTL effect as well as polygenic and environmental effects for all animals. One QTL was simulated on a randomly chosen SNP and accounted for 5%, 10% or 18% of the total variance. The power to detect a moderate-sized additive QTL (5% of the phenotypic variance) with 365 animals genotyped was 37% (p < 0.001). Most importantly, if pedigree structure was not accounted for, the number of false positives significantly increased above those expected by chance alone. Selective genotyping also resulted in a significant increase in false positives, even when pedigree structure was accounted for.

[1]  F. Schenkel,et al.  A genome scan to detect quantitative trait loci for economically important traits in Holstein cattle using two methods and a dense single nucleotide polymorphism map. , 2008, Journal of dairy science.

[2]  M. Goddard,et al.  Linkage Disequilibrium and Persistence of Phase in Holstein–Friesian, Jersey and Angus Cattle , 2008, Genetics.

[3]  David M. Evans,et al.  Genome-wide association analysis identifies 20 loci that influence adult height , 2008, Nature Genetics.

[4]  W. Barris,et al.  Extent of genome-wide linkage disequilibrium in Australian Holstein-Friesian cattle based on a high-density SNP panel , 2008, BMC Genomics.

[5]  J. Aerts,et al.  Whole genome linkage disequilibrium maps in cattle , 2007, BMC Genetics.

[6]  G. Lathrop,et al.  Genetic and Haplotypic Structure in 14 European and African Cattle Breeds , 2007, Genetics.

[7]  A. Reverter,et al.  A Validated Whole-Genome Association Study of Efficient Food Conversion in Cattle , 2007, Genetics.

[8]  R. Fernando,et al.  Power and Precision of Alternate Methods for Linkage Disequilibrium Mapping of Quantitative Trait Loci , 2007, Genetics.

[9]  D. Schaid Power and Sample Size for Testing Associations of Haplotypes with Complex Traits , 2006, Annals of human genetics.

[10]  N. Wray Allele frequencies and the r2 measure of linkage disequilibrium: impact on design and interpretation of association studies. , 2005, Twin research and human genetics : the official journal of the International Society for Twin Studies.

[11]  R. Fernando,et al.  Comparing Linkage Disequilibrium-Based Methods for Fine Mapping Quantitative Trait Loci , 2004, Genetics.

[12]  P. Visscher,et al.  Novel multilocus measure of linkage disequilibrium to estimate past effective population size. , 2003, Genome research.

[13]  J. Archer,et al.  Genetic and phenotypic variance and covariance components for feed intake, feed efficiency, and other postweaning traits in Angus cattle. , 2001, Journal of animal science.

[14]  M. Goddard,et al.  The distribution of the effects of genes affecting quantitative traits in livestock , 2001, Genetics Selection Evolution.

[15]  P. Sham,et al.  Power of linkage versus association analysis of quantitative traits, by use of variance-components models, for sibship data. , 2000, American journal of human genetics.

[16]  Jeanine J. Houwing-Duistermaat,et al.  Power of Selective Genotyping in Genetic Association Analyses of Quantitative Traits , 2000, Behavior genetics.

[17]  M. Mni,et al.  Extensive genome-wide linkage disequilibrium in cattle. , 2000, Genome research.

[18]  Gonçalo R. Abecasis,et al.  GOLD-Graphical Overview of Linkage Disequilibrium , 2000, Bioinform..

[19]  J. Pritchard,et al.  Use of unlinked genetic markers to detect population stratification in association studies. , 1999, American journal of human genetics.

[20]  Thomas L. Madden,et al.  Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. , 1997, Nucleic acids research.

[21]  L. Excoffier,et al.  Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. , 1995, Molecular biology and evolution.

[22]  R. Doerge,et al.  Empirical threshold values for quantitative trait mapping. , 1994, Genetics.

[23]  W. G. Hill,et al.  Linkage disequilibrium in finite populations , 1968, Theoretical and Applied Genetics.

[24]  R. Lewontin The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. , 1964, Genetics.

[25]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[26]  E. Lander,et al.  Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. , 1989, Genetics.