Detecting Marker-Disease Association by Testing for Hardy-Weinberg Disequilibrium at a Marker Locus

Abstract

We review and extend a recent suggestion that fine-scale localization of a disease-susceptibility locus for a complex disease be done on the basis of deviations from Hardy-Weinberg equilibrium among affected individuals. This deviation is driven by linkage disequilibrium between disease and marker loci in the whole population and requires a heterogeneous genetic basis for the disease. A finding of marker-locus Hardy-Weinberg disequilibrium therefore implies disease heterogeneity and marker-disease linkage disequilibrium. Although a lack of departure of Hardy-Weinberg disequilibrium at marker loci implies that disease susceptibilityweighted linkage disequilibria are zero, given disease heterogeneity, it does not follow that the usual measures of linkage disequilibrium are zero. For disease-susceptibility loci with more than two alleles, therefore, care is needed in the drawing of inferences from marker Hardy-Weinberg disequilibria.

Apolipoprotein E region molecular signatures of Alzheimer's disease

“…Specifically, the haplotype‐based method evaluates r as$r_{A,B}^h=D_{\mathit{AB}}/\sqrt{p_{A}false(1-p_{A}false)p_{B}false(1-p_{B}false)},$where p i ( i  =  A,B ) are allele frequencies in two SNPs, D AB  =  h 1 – p A p B is the LD coefficient, and h 1 is the frequency of a haplotype AB . This method assumes Hardy–Weinberg equilibrium (HWE), which may or may not hold in subsamples and/or at the haplotypic level, even when SNPs in a sample are in HWE (Nielsen, Ehm & Weir, 1998). Haplotype frequencies were evaluated using an expectation‐maximization algorithm ( haplo.stats package in r ).…”

“…In the case of HWE, $h_1^{\prime }=p_A{p}_B$ implies that $r_{A,B}^g=r_{A,B}^h$, so Δ AB is an unbiased estimate of the LD parameter D AB . Therefore, inequality Δ AB  ≠  D AB characterizes deviation from the HWE at the haplotypic level, which otherwise could be difficult to detect (Nielsen et al., 1998). …”

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

“…Hardy-Weinberg equilibrium was determined before analysis and was performed for quality control purposes rather than to evaluate if the genotypes met Mendelian expectation because all members of our study population have sickle cell disease. [43][44][45][46][47][48] SNPs that had more than 25% missing genotypes or less than 5% minor allele frequency were not considered in the analysis. This resulted in 280 SNPs being tested for association.…”

A case-based evaluation of SRD5A1, SRD5A2, AR, and ADRA1A as candidate genes for severity of BPH

“…¼ 4) was calculated for each pair to test the null hypothesis that the joint effects were multiplicative (statistical significance was two-tailed and defined as Po0.05). Similar to the single-locus test described by Nielsen et al, 46 this is a valid test for interaction in the absence of population LD. A hallmark of many genetic-based disorders is an earlier age of onset (eg, the occurrence of cancer at an unusually young age, relative to the typical age for the type of cancer, is suggestive of an inherited predisposition).…”