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

TLDR

Multiple locus association analyses are debated for their utility in identifying genomic regions influencing complex traits, particularly regarding how case/control genotypic data can assess allele–trait associations. This paper develops methods to test associations between estimated haplotype frequencies derived from multilocus genotype data and disease endpoints in case/control designs. The methods estimate haplotype frequencies without phase information, enabling comprehensive assessment of sequence or multi‑site variation associations, and were applied to APOE polymorphisms and Alzheimer’s disease using US and French case/control samples. The results confirm the APOE locus association with Alzheimer’s disease even when epsilon4 is absent from the tested haplotypes, showing that haplotype and LD‑induced associations can identify disease‑predisposing alleles in large, freely mixing populations via estimated haplotype frequency methods.

Abstract

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 epsilon 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.