Accounting for Linkage Disequilibrium among Markers in Linkage Analysis: Impact of Haplotype Frequency Estimation and Molecular Haplotypes for a Gene in a Candidate Region for Alzheimer’s Disease

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Abstract
Objectives: Linkage disequilibrium (LD) between closely spaced SNPs can be accommodated in linkage analysis by specifying the multi-SNP haplotype frequencies, if known. Phased haplotypes in candidate regions can provide gold standard haplotype frequency estimates, and may be of inherent interest as markers. We evaluated the effects of different methods of haplotype frequency estimation, and the use of marker phase information, on linkage analysis of a multi-SNP cluster in a candidate region for Alzheimer’s disease (AD). Methods: We performed parametric linkage analysis of a five-SNP cluster in extended pedigrees to compare the use of: (1) haplotype frequencies estimated by molecular phase determination, maximum likelihood estimation, or by assuming linkage equilibrium (LE); (2) AD families or controls as the frequency source; and (3) unphased or molecularly phased SNP data. Results: There was moderate to strong pairwise LD among the five SNPs. Falsely assuming LE substantially inflated the LOD score, but the method of haplotype frequency estimation and particular sample used made little difference provided that LD was accommodated. Use of phased haplotypes produced a modest increase in the LOD score over unphased SNPs. Conclusions: Ignoring LD between markers can lead to substantially inflated evidence for linkage in LOD score analysis of extended pedigrees with missing data. Use of marker phase information in linkage analysis may be important in disease studies where the costs of family recruitment and phenotyping greatly exceed the costs of phase determination.