A Generalized Sequential Bonferroni Procedure Using Smoothed Weights for Genome-Wide Association Studies Incorporating Information on Hardy-Weinberg Disequilibrium among Cases

Abstract

Background/Objectives: For genome-wide association studies (GWAS) with case-control designs, one of the most widely used association tests is the Cochran-Armitage (CA) trend test assuming an additive mode of inheritance. The CA trend test often has higher power than other association tests under additive and multiplicative disease models. However, it can have very low power under a recessive disease model in GWAS. Although tests (such as MAX3) robust to different genetic models have been developed, they often have relatively lower power than the CA trend test under additive and multiplicative models. The goal of this study is to propose an efficient method that not only has higher power than the CA trend test under dominant and recessive models but also maintains the power of the CA trend test under additive and multiplicative models. Methods: We employed the generalized sequential Bonferroni (GSB) procedure of Holm to incorporate information from a Hardy-Weinberg disequilibrium (HWD) test into the CA trend test based on estimating weights from the p values of the HWD test. We proposed to smooth the weights to reduce possible noise. Results and Conclusions: Results from extensive simulation studies showed that the proposed GSB procedure can achieve the goal described above.

Single Nucleotide Polymorphisms in Osteogenic Genes in Atrophic Delayed Fracture-Healing

“…At this stage, three SNPs (rs3758853 in MMP13, rs1143641 in IL1B, and rs2075554 in COL1A1) did not segregate in the population and were therefore excluded from the analysis. Finally, SNPs were tested for Hardy-Weinberg equilibrium, and eight were excluded because the Hardy-Weinberg p value was smaller than the Bonferroni-corrected level of 0.05/141 = 0.000355 [35][36][37][38][39][40][41] . In some cases, the exclusion resulted from a small minor-allele frequency (Table III).…”

Rare high-impact disease variants: properties and identifications

“…Therefore, even though a disease variant was identified through the current method, caution should be taken regarding the possible existence of another disease variant in high LD through r 2 . Possible solutions to identify all of the disease variants might be the observations of Hardy–Weinberg disequilibrium for disease variants (Lee, 2003; Song & Elston, 2006; Grover et al , 2010; Gao et al , 2012; Xu et al , 2012) or analyses of the variants of the gene locus that interact with the analyzed gene locus (Phillips, 2008; Cordell, 2009; Shin et al , 2012).…”

A Rapid Association Test Procedure Robust under Different Genetic Models Accounting for Population Stratification

“…Our simulation studies indicate that the existing robust test, MAX3-PC, can be computationally intensive for GWAS with a large number of SNPs and can have relatively lower power than the GA trend test when the underlying disease model is additive or multiplicative. Our proposed method can be viewed as an extension to account for population stratification of our previously proposed generalized sequential Bonferroni (GSB) procedure for GWAS in homogeneous populations [25]. …”