Accounting for unmeasured population substructure in case-control studies of genetic association using a novel latent-class model.

We propose a novel latent-class approach to detect and account for population stratification in a case-control study of association between a candidate gene and a disease. In our approach, population substructure is detected and accounted for using data on additional loci that are in linkage equilibrium within subpopulations but have alleles that vary in frequency between subpopulations. We have tested our approach using simulated data based on allele frequencies in 12 short tandem repeat (STR) loci in four populations in Argentina.

[1]  R. Tibshirani,et al.  An Introduction to the Bootstrap , 1995 .

[2]  W. Ewens,et al.  The transmission/disequilibrium test: history, subdivision, and admixture. , 1995, American journal of human genetics.

[3]  W. Ewens,et al.  Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). , 1993, American journal of human genetics.

[4]  K. Liang,et al.  On estimating HLA/disease association with application to a study of aplastic anemia. , 1991, Biometrics.

[5]  D. Seminara,et al.  Participation in the cooperative family registry for breast cancer studies: issues of informed consent. , 2000, Journal of the National Cancer Institute.

[6]  N. Rothman,et al.  Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. , 2000, Journal of the National Cancer Institute.

[7]  N E Morton,et al.  Tests and estimates of allelic association in complex inheritance. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Williams,et al.  Gm3;5,13,14 and type 2 diabetes mellitus: an association in American Indians with genetic admixture. , 1988, American journal of human genetics.

[9]  W D Flanders,et al.  Transmission disequilibrium test (TDT) when only one parent is available: the 1-TDT. , 1999, American journal of epidemiology.

[10]  B Devlin,et al.  Genomic control for association studies: a semiparametric test to detect excess-haplotype sharing. , 2000, Biostatistics.

[11]  D. Corach,et al.  Comparison of allele frequencies of eight STR loci from Argentinian Amerindian and European populations. , 1998, Human biology.

[12]  E. Boerwinkle,et al.  Polymorphic markers in apolipoprotein C-III gene flanking regions and hypertriglyceridemia. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[13]  D. Rubin,et al.  Reducing Bias in Observational Studies Using Subclassification on the Propensity Score , 1984 .

[14]  J. Witte,et al.  Genetic dissection of complex traits. , 1994, Nature genetics.

[15]  J. Stephens,et al.  Polymorphic admixture typing in human ethnic populations. , 1994, American journal of human genetics.

[16]  D. Allison,et al.  Estimating African American admixture proportions by use of population-specific alleles. , 1998, American journal of human genetics.

[17]  N Risch,et al.  The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases I. DNA pooling. , 1998, Genome research.

[18]  D. Corach,et al.  Reference database of hypervariable genetic markers of Argentina: Application for molecular anthropology and forensic casework , 1999, Electrophoresis.

[19]  P. Donnelly,et al.  Association mapping in structured populations. , 2000, American journal of human genetics.

[20]  H. Morgenstern,et al.  Epidemiologic Research: Principles and Quantitative Methods. , 1983 .

[21]  C C Li,et al.  Population subdivision with respect to multiple alleles , 1969, Annals of human genetics.

[22]  L. Jin,et al.  Ethnic-affiliation estimation by use of population-specific DNA markers. , 1997, American journal of human genetics.

[23]  P. Sasieni.  From genotypes to genes: doubling the sample size. , 1997, Biometrics.

[24]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[25]  W. Ewens,et al.  A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. , 1998, American journal of human genetics.

[26]  J. Stephens,et al.  Mapping by admixture linkage disequilibrium in human populations: limits and guidelines. , 1994, American journal of human genetics.

[27]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[28]  K. Roeder,et al.  The power of genomic control. , 2000, American journal of human genetics.

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

[30]  P. Donnelly,et al.  Inference of population structure using multilocus genotype data. , 2000, Genetics.