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. 2008 Dec 22:9:90.
doi: 10.1186/1471-2156-9-90.

A systematic search for SNPs/haplotypes associated with disease phenotypes using a haplotype-based stepwise procedure

Yin Yang  1 , Shuying Sue Li, Jason W Chien, Jessica Andriesen, Lue Ping Zhao
Affiliations

A systematic search for SNPs/haplotypes associated with disease phenotypes using a haplotype-based stepwise procedure

Yin Yang et al. BMC Genet. .

Abstract

Background: Genotyping technologies enable us to genotype multiple Single Nucleotide Polymorphisms (SNPs) within selected genes/regions, providing data for haplotype association analysis. While haplotype-based association analysis is powerful for detecting untyped causal alleles in linkage-disequilibrium (LD) with neighboring SNPs/haplotypes, the inclusion of extraneous SNPs could reduce its power by increasing the number of haplotypes with each additional SNP.

Methods: Here, we propose a haplotype-based stepwise procedure (HBSP) to eliminate extraneous SNPs. To evaluate its properties, we applied HBSP to both simulated and real data, generated from a study of genetic associations of the bactericidal/permeability-increasing (BPI) gene with pulmonary function in a cohort of patients following bone marrow transplantation.

Results: Under the null hypothesis, use of the HBSP gave results that retained the desired false positive error rates when multiple comparisons were considered. Under various alternative hypotheses, HBSP had adequate power to detect modest genetic associations in case-control studies with 500, 1,000 or 2,000 subjects. In the current application, HBSP led to the identification of two specific SNPs with a positive validation.

Conclusion: These results demonstrate that HBSP retains the essence of haplotype-based association analysis while improving analytic power by excluding extraneous SNPs. Minimizing the number of SNPs also enables simpler interpretation and more cost-effective applications.

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Figures

Figure 1
Figure 1
Outline of the three computational algorithms for the stepwise selection of SNPs. (A) Forward selection procedure. (B) Backward selection procedure. (C) Hybrid Selection Procedure.
Figure 2
Figure 2
LD patterns among 15 simulated SNPs and their haplotype block boundaries, indicated by solid lines: (a) Standard D'/LOD pattern is shown, and (b) the LD pattern with r2 using confidence intervals.
See this image and copyright information in PMC

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