Characterization of linkage disequilibrium structure, mutation history, and tagging SNPs, and their use in association analyses: ELAC2 and familial early-onset prostate cancer
✍ Scribed by Nicola J. Camp; Jeff Swensen; Benjamin D. Horne; James M. Farnham; Alun Thomas; Lisa A. Cannon-Albright; Sean V. Tavtigian
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 130 KB
- Volume
- 28
- Category
- Article
- ISSN
- 0741-0395
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✦ Synopsis
Abstract
In association analyses, it is critical that informative single‐nucleotide polymorphisms (SNPs) be selected for study and utilized appropriately. We sequenced 38 kb, including exons of ELAC2, promoter region and conserved upstream intergenic sequences. A comprehensive characterization of linkage disequilibrium (LD) structure and mutation history was performed using our principal components analysis (PCA) method and a phylogenetic analysis. We identified a complex pattern of LD structure consistent with the occurrence of both recombination and mutation events within ELAC2. Four overlapping and noncontiguous LD groups were defined. Eight tagging SNPs (__t__SNPs) were identified, accounting for over 90% of the genetic variation of the 19 total variants. We tested associations between familial early‐onset prostate cancer (PRCA) and each variant independently and in haplotypes. We performed these tests using all 19 variants and the 8 __t__SNPs; the results using __t__SNP haplotypes accurately represent the association evidence for the full haplotypes. We observed increased evidence for association when SNPs were analyzed in haplotypes. The phylogenetic analysis indicated three haplotypes, clustered farthest from the root‐node, all of which were found more often in cases than controls. These three haplotypes together showed the best evidence of association with familial, early‐onset PRCA (P=0.0024; odds ratio=2.23; 95% CI, 1.33–3.74), indicating possible allelic heterogeneity. Our results suggest that 8 __t__SNPs are required to comprehensively assess associations in ELAC2, and that haplotypes should be considered for analysis, and that a knowledge of mutation history may be helpful in parsing allelic heterogeneity and suggesting combinations of haplotypes to be tested. Genet. Epidemiol. © 2004 Wiley‐Liss, Inc.