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. 2011 Nov 29;5 Suppl 9(Suppl 9):S96.
doi: 10.1186/1753-6561-5-S9-S96.

Detecting disease rare alleles using single SNPs in families and haplotyping in unrelated subjects from the Genetic Analysis Workshop 17 data

Aldi T Kraja  1 , Jacek Czajkowski, Mary F Feitosa, Ingrid B Borecki, Michael A Province
Affiliations

Detecting disease rare alleles using single SNPs in families and haplotyping in unrelated subjects from the Genetic Analysis Workshop 17 data

Aldi T Kraja et al. BMC Proc. .

Abstract

We present an evaluation of discovery power for two association tests that work well with common alleles but are applied to the Genetic Analysis Workshop 17 simulations with rare causative single-nucleotide polymorphisms (SNPs) (minor allele frequency [MAF] < 1%). The methods used were genome-wide single-SNP association tests based on a linear mixed-effects model for discovery and applied to the familial sample and sliding windows haplotype association tests for replication, implemented within causative genes in the unrelated individuals sample. Both methods are evaluated with respect to the simulated trait Q2. The linear mixed-effects model and haplotype association tests failed to detect the rare alleles of the simulated associations. In contrast, the linear mixed-effects model and haplotype association tests detected effects for the most important simulated SNPs with MAF > 1%. We conclude that these findings reflect inadequate statistical power (the result of small simulated samples) for the complex genetic model that underlies these data.

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Figures

Figure 1
Figure 1
Genome-wide linear mixed effects additive model association test results of 200 replications of family-based cohort data on Q2 residuals. None of the SNPs’ −log10p mean values passed the 5.4 genome-wide threshold. Sens. = sensitivity. Red triangles mark chromosomes that were simulated with Q2 causative SNPs (72 of them in 13 genes).
Figure 2
Figure 2
Sensitivity and specificity of SNPs discovery by using the linear mixed-effects additive model on gene bases for the Q2 simulated trait
Figure 3
Figure 3
Three-marker sliding windows haplotypes for the LPL gene. Haplotypes containing the SNP C8S442, although close to rare haplotypes (frequency 1.6), showed distinct association with Q2 trait.
Figure 4
Figure 4
Two-marker sliding windows haplotypes for genes VNN3 and VNN1. Haplotypes containing C6S5380 and C6S5449 show distinct association with Q2.
See this image and copyright information in PMC

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