Testing for population subdivision and association in four case-control studies - PubMed (original) (raw)

Testing for population subdivision and association in four case-control studies

Kristin G Ardlie et al. Am J Hum Genet. 2002 Aug.

Abstract

Population structure has been presumed to cause many of the unreplicated disease-marker associations reported in the literature, yet few actual case-control studies have been evaluated for the presence of structure. Here, we examine four moderate case-control samples, comprising 3,472 individuals, to determine if detectable population subdivision is present. The four population samples include: 500 U.S. whites and 236 African Americans with hypertension; and 500 U.S. whites and 500 Polish whites with type 2 diabetes, all with matched control subjects. Both diabetes populations were typed for the PPARg Pro12Ala polymorphism, to replicate this well-supported association (Altshuler et al. 2000). In each of the four samples, we tested for structure, using the sum of the case-control allele frequency chi(2) statistics for 9 STR and 35 SNP markers (Pritchard and Rosenberg 1999). We found weak evidence for population structure in the African American sample only, but further refinement of the sample, to include only individuals with U.S.-born parents and grandparents, eliminated the stratification. Our examples provide insight into the factors affecting the replication of association studies and suggest that carefully matched, moderate-sized case-control samples in cosmopolitan U.S. and European populations are unlikely to contain levels of structure that would result in significantly inflated numbers of false-positive associations. We explore the role that extreme differences in power among studies, due to sample size and risk-allele frequency differences, may play in the replication problem.

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Figure 1

Figure 1

Power to detect an allelic association for 500 case subjects and 500 control subjects under a multiplicative genetic model with genotypic risk ratio 1.25, by risk-allele frequency and disease prevalence. Allele frequencies for case and control subjects were determined under the given genetic models; power to detect the difference in allele frequencies was calculated for the exact test for a 2 × 2 contingency table, by the method of Walters (1979).

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References

Electronic-Database Information

    1. Global Repository at GCI, http://www.genomicsinc.com (for case-control samples)
    1. SNP Consortium, http://snp.cshl.org/allele_frequency_project/ (for biallelic SNPs)
    1. World Health Organization, http://www.who.int/ncd/dia/databases2.htm#t3

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