Fine‐scale mapping using Hardy–Weinberg disequilibrium

Abstract

summaryHardy-Weinberg disequilibrium (HWD) among affected individuals has recently been proposed for fine-scale mapping of disease susceptibility genes. We investigate the statistical properties of several available HWD measures and develop a new HWD measure J for fine-scale mapping. It is shown both theoretically and through simulations that the available HWD measures depend not only on the genetic distance between the marker locus of interest and the disease susceptibility locus, but also on the allele frequencies at the marker locus. On the contrary, the new measure is not affected by the allele frequencies at the marker locus under the following assumptions: (a) there is initial complete linkage disequilibrium between the marker and the disease loci, (b) there are no new mutations at the marker and the disease loci, and (c) the population under study is large. We develop a novel method to estimate the location of the disease susceptibility gene based on the HWD measure J. The estimator is robust to low mutation rates at the marker and the disease loci. We compare the standard error of the estimated disease gene loci using P excess for case-control studies with the standard error using J for case-only studies under various disease models.The newly developed method is successfully applied to a data set on hereditary haemochromatosis (HH).introduction

ADH4 Gene Variation is Associated with Alcohol Dependence and Drug Dependence in European Americans: Results from HWD Tests and Case–Control Association Studies

“…The markers in LD with the risk locus may be in HWD as well; alternatively, HWD may indicate that the markers in HWD are in close proximity to the disease risk locus. The detection of HWD has recently been shown to be useful as a method for detecting genephenotype association (Feder et al, 1996;Nielsen et al, 1998;Jiang et al, 2001;Hoh et al, 2001;Lee, 2003;Hao et al, 2004;Wittke-Thompson et al, 2005;Luo et al, 2005). The present study provides an additional illustration of this approach.…”

“…Thus, in the present study, the pairwise LD between any two ADH4 markers was analyzed separately for EAs and AAs. The D (Feder et al, 1996;Nielsen et al, 1998;Jiang et al, 2001;Hoh et al, 2001;Lee, 2003;Hao et al, 2004). The HWD test as an association method in cases only has been reported to be more powerful than a case-control study, especially for a recessive model (Nielsen et al, 1998).…”

“…According to the F values (Feder et al, 1996), which reflect the extent of HWD, SNP6 and SNP2 were the markers closest to the risk loci for alcohol dependence and drug dependence (including cocaine and opioid dependence), respectively. After correcting for the influence of marker allele frequency on HWD, that is, according to the J values (Jiang et al, 2001), which also reflect the extent of HWD and are equivalent to P excess in a case-control design (Devlin and Risch, 1995), SNP6 is the marker closest to the risk loci for both alcohol dependence and drug dependence.…”

Genotypes over-represented among college students are linked to better cognitive abilities and socioemotional adjustment

“…Third, it may indicate that the sample was not biased because of a sampling problem, but ''biased'' because it is a special sample (e.g., patients). The last possibility has been explored recently to discover disease genes (Feder et al 1996;Nielsen et al 1998;Jiang et al 2001;Lee 2003;.…”

Robust Indices of Hardy-Weinberg Disequilibrium for QTL Fine Mapping

“…Fine-scale mapping with HWD for dichotomous traits was examined and extended theoretically [2]. The original HWD measure depends on the allele frequencies at the marker loci, which may introduce some noise and even bias in fine mapping of genes for complex traits [3]. Therefore, Jiang et al [3] introduced two new HWD measures that have the advantage of being independent of the marker allele frequencies for fine mapping complex disease genes.…”