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Evaluating coverage of genome-wide association studies


Genome-wide association studies involving hundreds of thousands of SNPs in thousands of cases and controls are now underway. The first of many analytical challenges in these studies involves the choice of SNPs to genotype. It is not practical to construct a different panel of tag SNPs for each study, so the first generation of genome-wide scans will use predefined, commercially available marker panels, which will in part dictate their success or failure. We compare different approaches in use today, and show that although many of them provide substantial coverage of common variation in non-African populations, the precise extent is strongly dependent on the frequencies of alleles of interest and on specific considerations of study design. Overall, despite substantial differences in genotyping technologies, marker selection strategies and number of markers assayed, the first-generation high-throughput platforms all offer similar levels of genome coverage.

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Figure 1: Genomic coverage by maximally efficient (pairwise) tag sets for three HapMap panels and three r2 cutoffs.
Figure 2: Minor allele frequency in CEU for 900,000 polymorphic Phase I HapMap SNPs, 2 million distinct polymorphic SNPs added during the second phase of HapMap and 10,000 polymorphic ENCODE SNPs (which approximate the underlying frequency distribution in the genome).
Figure 3: Coverage of common variation in the Phase II HapMap by the Affymetrix 500K and Illumina HumanHap300 products plotted as a function of random genotype failure rate.
Figure 4

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We wish to thank M. Daly, I. Pe'er, L. Palmer, M. Barnes and the WTCCC analysis group, particularly D. Clayton and P. Donnelly, for discussions on many of these topics. We thank D. Evans for comments on the manuscript. We also thank the investigators and participants in the International HapMap project for generating the unique data set and making it available to the scientific community. The authors are supported by the Wellcome Trust, the US National Institutes of Health and a grant from the European Union (MolPAGE).

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Correspondence to Lon R Cardon.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Coverage by r2 threshold. (PDF 29 kb)

Supplementary Figure 2

HapMap and ENCODE allele frequencies. (PDF 27 kb)

Supplementary Methods (PDF 33 kb)

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Barrett, J., Cardon, L. Evaluating coverage of genome-wide association studies. Nat Genet 38, 659–662 (2006).

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