Haplotype Frequencies In Controls Research Articles

SimGWAS: a fast method for simulation of large scale case-control GWAS summary statistics.

MotivationMethods for analysis of GWAS summary statistics have encouraged data sharing and democratized the analysis of different diseases. Ideal validation for such methods is application to simulated data, where some ‘truth’ is known. As GWAS increase in size, so does the computational complexity of such evaluations; standard practice repeatedly simulates and analyses genotype data for all individuals in an example study.ResultsWe have developed a novel method based on an alternative approach, directly simulating GWAS summary data, without individual data as an intermediate step. We mathematically derive the expected statistics for any set of causal variants and their effect sizes, conditional upon control haplotype frequencies (available from public reference datasets). Simulation of GWAS summary output can be conducted independently of sample size by simulating random variates about these expected values. Across a range of scenarios, our method, produces very similar output to that from simulating individual genotypes with a substantial gain in speed even for modest sample sizes. Fast simulation of GWAS summary statistics will enable more complete and rapid evaluation of summary statistic methods as well as opening new potential avenues of research in fine mapping and gene set enrichment analysis.Availability and implementationOur method is available under a GPL license as an R package from http://github.com/chr1swallace/simGWAS.Supplementary information Supplementary data are available at Bioinformatics online.

Minor differences in haplotype frequency estimates can produce very large differences in heterogeneity test statistics

BackgroundTests for association between a haplotype and disease are commonly performed using a likelihood ratio test for heterogeneity between case and control haplotype frequencies. Using data from a study of association between heroin dependence and the DRD2 gene, we obtained estimated haplotype frequencies and the associated likelihood ratio statistic using two different computer programs, MLOCUS and GENECOUNTING. We also carried out permutation testing to assess the empirical significance of the results obtained.ResultsBoth programs yielded similar, though not identical, estimates for the haplotype frequencies. MLOCUS produced a p value of 1.8*10-15 and GENECOUNTING produced a p value of 5.4*10-4. Permutation testing produced a p value 2.8*10-4.ConclusionThe fact that very large differences occur between the likelihood ratio statistics from the two programs may reflect the fact that the haplotype frequencies for the combined group are not constrained to be equal to the weighted averages of the frequencies for the cases and controls, as they would be if they were directly observed rather than being estimated. Minor differences in haplotype frequency estimates can result in very large differences in the likelihood ratio statistic and associated p value.

A Simple Loglinear Model for Haplotype Effects in a Case-Control Study Involving Two Unphased Genotypes

Because haplotypes may parsimoniously summarize the effect of genes on disease, there is great interest in using haplotypes in case-control studies of unphased genotype data. Previous methods for investigating haplotypes effects in case-control studies have not allowed for both of the following two scenarios that could have a large impact on results (i) departures from Hardy-Weinberg equilibrium in controls as well as cases, and (ii) an interactive effect of haplotypes and environmental covariates on the probability of disease. A new method is proposed that generalizes the model of Epstein and Satten to incorporate both (i) and (ii). Computations are relatively simple involving a single loglinear design matrix for parameters modeling the distribution of haplotype frequencies in controls, parameters modeling the effect of haplotypes and covariate-haplotype interactions on disease, and nuisance parameters required for correct inference. Based on simulations with realistic sample sizes, the method is recommended with data from two genotypes, a recessive or dominant model linking haplotypes to disease, and estimates of haplotype effects among haplotypes with a frequency greater than 10%. The methodology is most useful with candidate genotype pairs or for searching through pairs of genotypes when scenarios (i) and (ii) are likely. An example without a covariate illustrates the importance of modeling a departure from Hardy-Weinberg equilibrium in controls.

HLA-DQ relative risks for coeliac disease in European populations: a study of the European Genetics Cluster on Coeliac Disease.

Coeliac disease is an enteropathy due to an intolerance to gluten. The association between HLA-DQ genes and CD is well established. The majority of patients carry the HLA-DQ heterodimer encoded by DQA1*05/DQB1*02, either in cis or in trans. The remaining patients carry either part of the DQ heterodimer or DQA1*03-DQB1*0302. The aim of the study was to estimate the risks associated with different DQ genotypes in European populations. HLA information was available for 470 trio families from four countries: France (117), Italy (128), and Norway and Sweden (225). Five DQA1-DQB1 haplotypes were considered and control haplotype frequencies were estimated from the set of parental haplotypes not transmitted to the affected child. The possible genotypes were grouped into five genotype groups, based on the hierarchy of risk reported in the literature. A north-south gradient in the genotype group frequencies is observed in probands: homogeneity is strongly rejected between all country pairs. For each country, the relative risks associated with each genotype group were computed taking into account the control haplotype frequencies. Homogeneity of relative risks between countries was tested pairwise by maximum likelihood ratio statistics. The hypothesis of homogeneity of relative risks is rejected (P is approximately 10(-6)) for all country pairs. In conclusion, the gradient in the genotype group frequencies in probands is not only due to differences in haplotype frequencies but also due to differences in genotype relative risks in the studied populations; the relative risks associated with each DQ genotype group are different between northern and southern European countries; neither are they ordered in the same way.

A haplotype at the DBH locus, associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia.

Low levels of dopamine beta-hydroxylase (DbetaH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DbetaH level is a stable, genetically controlled trait. DBH, the locus encoding DbetaH protein, is the major quantitative trait locus controlling plasma and CSF DbetaH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DbetaH in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5'-ins/del, located approximately 3 kb 5' to the DBH transcriptional start site, significantly associates with plasma DbetaH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DbetaH levels, demonstrated that alleles of similar association to DbetaH levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-DbetaH-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia. We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to DbetaH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.

HLA haplotypes in non-familial rheumatoid arthritis.

The frequencies of HLA-A, B, C, DR, and BF haplotypes in 44 unrelated Caucasian patients with definite seropositive rheumatoid arthritis (RA) were compared with haplotype frequencies in controls. Overall, the patients had an increased risk for HLA-DR4, DR3, and DR2 antigens, but frequencies of certain DR4 or DR3 haplotypes were not increased, suggesting the importance of other HLA loci for the evaluation of risk. The presence of DR4 alone was not found to produce an increased risk for RA since the frequencies of certain DR4 haplotypes were similar in patients and controls. Increased frequencies of HLA-B18, DR4, HLA-B15, DR4, and HLA-A1, B8, Cw7, DR3 haplotypes were found in patients. RA susceptibility has been found to be associated with the last two haplotypes in some studies of multiple case families, suggesting that similar genetic mechanisms may underlie the disease in familial and sporadic forms.