A powerful method of combining measures of association and Hardy–Weinberg disequilibrium for fine‐mapping in case‐control studies

We present a new method for fine‐mapping a disease susceptibility locus using a case‐control design. The new method, termed the ‘weighted average (WA) statistic’, averages the Cochran–Armitage (CA) trend test statistic and the difference between the Hardy Weinberg disequilibrium test statistics (the HWD trend) for cases and controls. The main features of the WA statistic are that it mitigates against the weaknesses, and maintains the strong points, of both the CA trend test and the HWD trend test. To allow for the extra variance induced by population structure and cryptic relatedness, the WA statistic can be adjusted for variance inflation. Based on the results of a simulation study, when there is no population structure the WA test statistic shows good performance under a variety of genetic disease models. When there is population structure, the adjusted WA statistic maintains the correct probability of type I error. Under all genetic disease models investigated, the adjusted WA statistic has better power than the adjusted CA trend test, the HWD trend test or the product of the adjusted CA trend test and the HWD trend test statistics. Copyright © 2005 John Wiley & Sons, Ltd.

[1]  N. Risch.  Searching for genetic determinants in the new millennium , 2000, Nature.

[2]  G A Satten,et al.  Accounting for unmeasured population substructure in case-control studies of genetic association using a novel latent-class model. , 2001, American journal of human genetics.

[3]  D. Schaid,et al.  Case-Control Studies of Genetic Markers: Power and Sample Size Approximations for Armitage’s Test for Trend , 2001, Human Heredity.

[4]  S. Zhang,et al.  Quantitative similarity-based association tests using population samples. , 2001, American journal of human genetics.

[5]  M. Daly,et al.  A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms , 2001, Nature.

[6]  R. Elston,et al.  Tests for a Disease-susceptibility Locus allowing for an Inbreeding Coefficient (F) , 2003, Genetica.

[7]  M. Kimura,et al.  An introduction to population genetics theory , 1971 .

[8]  Wei-Min Chen,et al.  QTL fine mapping by measuring and testing for Hardy-Weinberg and linkage disequilibrium at a series of linked marker loci in extreme samples of populations. , 2000, American journal of human genetics.

[9]  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.

[10]  P. Armitage.  Tests for Linear Trends in Proportions and Frequencies , 1955 .

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

[12]  Xiaofeng Zhu,et al.  Association mapping, using a mixture model for complex traits , 2002, Genetic epidemiology.

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

[14]  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.

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

[16]  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.

[17]  David R. Cox.  The analysis of binary data , 1970 .

[18]  J. B. S. Haldane,et al.  The probable errors of calculated linkage values, and the most accurate method of determining gametic from certain zygotic series , 1919, Journal of Genetics.

[19]  R. Jiang,et al.  Fine‐scale mapping using Hardy–Weinberg disequilibrium , 2001, Annals of human genetics.

[20]  Eric S. Lander,et al.  The diastrophic dysplasia gene encodes a novel sulfate transporter: Positional cloning by fine-structure linkage disequilibrium mapping , 1994, Cell.

[21]  D. Reich,et al.  Detecting association in a case‐control study while correcting for population stratification , 2001, Genetic epidemiology.

[22]  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.

[23]  M. C. Ellis,et al.  A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis , 1996, Nature Genetics.

[24]  L. Tsui,et al.  Erratum: Identification of the Cystic Fibrosis Gene: Genetic Analysis , 1989, Science.

[25]  Eric Lander,et al.  Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland , 1992, Nature Genetics.

[26]  C. Falk,et al.  Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations , 1987, Annals of human genetics.

[27]  D. Gudbjartsson,et al.  A high-resolution recombination map of the human genome , 2002, Nature Genetics.

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

[29]  M. Ehm,et al.  Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. , 1998, American journal of human genetics.

[30]  J. Witte,et al.  Hierarchical modeling of linkage disequilibrium: genetic structure and spatial relations. , 2003, American journal of human genetics.

[31]  R. Myers,et al.  Progressive myoclonus epilepsy EPM1 locus maps to a 175-kb interval in distal 21q. , 1996, American journal of human genetics.

[32]  Robert C. Elston,et al.  On Fisher's Method of Combining p-Values , 1991 .

[33]  N M Laird,et al.  A discordant-sibship test for disequilibrium and linkage: no need for parental data. , 1998, American journal of human genetics.

[34]  W. G. Cochran.  Some Methods for Strengthening the Common χ 2 Tests , 1954 .

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

[36]  J. Ott,et al.  Trimming, weighting, and grouping SNPs in human case-control association studies. , 2001, Genome research.

[37]  M. MacDonald,et al.  Complex patterns of linkage disequilibrium in the Huntington disease region. , 1991, American journal of human genetics.

[38]  D. Curtis,et al.  Use of siblings as controls in case‐control association studies , 1997, Annals of human genetics.

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

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