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Vol. 11, Issue 1, 143-151, January 2001

METHODS
Genetic Analysis of Case/Control Data Using Estimated Haplotype Frequencies: Application to APOE Locus Variation and Alzheimer's Disease

Daniele Fallin,1,6 Annick Cohen,3 Laurent Essioux,2 Ilya Chumakov,3 Marta Blumenfeld,3 Daniel Cohen,3 and Nicholas J. Schork1,2,4,5,6,7

1 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44109, USA; 2 Department of Statistical Genomics, Genset Corporation, La Jolla, California 92037, USA; 3 Genset SA, Paris 75008, France; 4 Department of Biostatistics and Program for Population Genetics, Harvard University, Boston, Massachusetts 02115, USA; 5 The Jackson Laboratory, Bar Harbor, Maine 04609, USA

There is growing debate over the utility of multiple locus association analyses in the identification of genomic regions harboring sequence variants that influence common complex traits such as hypertension and diabetes. Much of this debate concerns the manner in which one can use the genotypic information from individuals gathered in simple sampling frameworks, such as the case/control designs, to actually assess the association between alleles in a particular genomic region and a trait. In this paper we describe methods for testing associations between estimated haplotype frequencies derived from multilocus genotype data and disease endpoints assuming a simple case/control sampling design. These proposed methods overcome the lack of phase information usually associated with samples of unrelated individuals and provide a comprehensive way of assessing the relationship between sequence or multiple-site variation and traits and diseases within populations. We applied the proposed methods in a study of the relationship between polymorphisms within the APOE gene region and Alzheimer's disease. Cases and controls for this study were collected from the United States and France. Our results confirm the known association between the APOE locus and Alzheimer's disease, even when the varepsilon 4 polymorphism is not contained in the tested haplotypes. This suggests that, in certain situations, haplotype information and linkage disequilibrium-induced associations between polymorphic loci that neighbor loci harboring functional sequence variants can be exploited to identify disease-predisposing alleles in large, freely mixing populations via estimated haplotype frequency methods.


6 These authors contributed equally to this work.

7 Corresponding author.


11:143-151 ©2001 by Cold Spring Harbor Laboratory Press  ISSN 1088-9051/01 $5.00

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