Abstract
Several variants have been implicated earlier on ULK4 and MAP4 genes on chromosome 3 to be associated with hypertension. As a natural follow-up step, we explore association of haplotypes in those genes. We consider the Genetic Analysis Workshop 19 real data on unrelated individuals and analyze haplotype blocks of 5 single-nucleotide polymorphisms through a sliding window approach. We apply 4 haplotype association methods—haplo.score, haplo.glm, hapassoc, and logistic Bayesian LASSO (LBL)—and for comparison, sequence kernel association test (SKAT) and its variants. We find several rare haplotype blocks to be associated. To get an idea about the false-positive proportions, we also analyzed the data after permuting the case-control status of individuals. We found that LBL, unlike the other methods, maintains low false-positive rates in presence of rare haplotypes. Thus, we conclude that the haplotypes found to be associated by LBL are more likely to be true positive. SKAT and its variants did not find significance on either gene.
Highlights
Past studies have implicated several variants on chromosome 3, in particular, on genes ULK4 and MAP4, as being associated with blood pressure and hypertension [1,2,3,4,5,6,7,8,9]
We report the results for ULK4 and MAP4 genes separately
ULK4 gene There are 70 single-nucleotide polymorphism (SNP). and so, with a sliding window of 5 SNPs, we analyzed a total of 66 haplotype blocks
Summary
Past studies have implicated several variants on chromosome 3, in particular, on genes ULK4 and MAP4, as being associated with blood pressure and hypertension [1,2,3,4,5,6,7,8,9]. Haplotype-based methods can be more powerful than single single-nucleotide polymorphism (SNP) methods especially when the causal variants are not genotyped or multiple variants act in cis [10,11,12]. In some situations, they have increased power over the recently developed popular “collapsing” methods for detecting rare variant associations [13,14,15]. A majority of SNPs in the GAW19 data set are rare; for example, less than 3 % of variants on chromosome 3 have a minor allele frequency (MAF) of 0.01 or more, so when rare SNPs are combined to form haplotype blocks, the haplotypes will be even rarer. It is important to use a haplotype association method that can handle rare haplotypes
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