Jan 28, 2019 marginal tests based on individual snps are routinely used in genetic association studies. Studies have shown that methods based on haplotypes may provide more power and accuracy in disease gene mapping than those based on single markers akey 2001, botstein 2003, fallin 2001, kankova 2005. Genome, linkage, association, haplotype, adhd, snp. Request pdf haplotype uncertaint y in association st udies inferring haplotypes from genotype data is commonly undertaken in population genetic association studies. Request pdf haplotype analysis in populationbased association studies this paper describes how to use the command hapipf and introduces the command profhap written for stata that analyzes. Studies of common diseases have fallen into two broad categories. Modeling haplotypehaplotype interactions in casecontrol. Several studies of haplotype structures in the human genome in various populations have. The haplotype formed by the dqa10501 and dqb10201 alleles also known as haplotype dq2. Haplotype analyses linkage disequilibrium assessment diseasegene discovery genetic demography chromosomal evolution studies why haplotypes haplotypes are more powerful discriminators between cases and controls in disease association studies use of haplotypes in disease association studies reduces. The aim of the present study was to compare the power of single nucleotide polymorphism snpbased genomewide association study. The plant genome abstract original research comparing.
An integrated gwas procedure, considering singlelocus and multilocus gwas approaches jointly, may improve the capacity of association studies to detect key qtls and to provide a more complete picture of the genetic architecture of complex traits in barley. In this study, data from the gwas for these candidate genes were reanalysed as haplotypes. Louis, missouri 634899, variagenics, cambridge, massachusetts 029. These methods, however, have been rarely discussed in. Haplotype analysis in population genetics and association. We examined the validity of the application of the likelihoodbased algorithm, which was originally developed to analyze the data from cohort studies or clinical trials, to the data from casecontrol studies. Because obtaining haplotype information directly from experiments can be cost prohibitive in most studies, especially in large scale studies, haplotype analysis presents many unique challenges. Marginal tests based on individual snps are routinely used in genetic association studies. Several single nucleotide polymorphism snp set approaches have been proposed to solve this problem.
Although prospective logistic regression is the standard method of analysis for casecontrol data, it has been recently noted that. Thesias testing haplotype effects in association studies is a popular software for carrying haplotype association analysis in unrelated individuals. The problem is closely related to the complex gene compositions comprising multiple alleles, such as haplotypes. Oct 27, 2005 studies of common diseases have fallen into two broad categories. Recent studies have shown that the human genome has a haplotype block structure, such that it can be divided into discrete blocks of limited haplotype diversity. Wholegenome association studies present many new statistical and computational challenges due to the large quantity of data obtained. In particular, we consider the em and wem algorithm as two representatives of haplotype based approaches because of their easy implementation. Likelihoodbased inference on haplotype effects in genetic. Pdf detecting haplotype effects in genomewide association. Skat aggregates individual score test statistics of snps in a snp set and efficiently computes snpset level pvalues, e. Linn department of biostatistics, university of north carolina, chapel hill, north carolina exploring the associations between haplotypes and disease phenotypes is an important step toward the discovery of genes that influence complex human diseases.
Previous studies in cattle have suggested that the benefi t of haplotype analysis may diminish at high marker densities grapes et al. Based on a theoretical model, population genetics simulations and analysis of a central corneal thickness cct genome wide association study gwas data set we have shown that combined genotype and haplotype approach has a high potential utility for applications in association studies. By incorporating the profile likelihood approachoflin et al. Simulation studies show that the proposed estimator has satisfactory finitesample performances. Haplotypebased association analysis in cohort studies of unrelated individuals d. In genome wide association studies gwas, haplotype analyses of snp data are neglected in favour of single point analysis of associations. Nov 01, 2006 the use of haplotype information in casecontrol studies is an area of focus for the research on the association between phenotypes and genetic polymorphisms. Nov 30, 2017 genomewide association studies using genotype data have had limited success in the identification of variants associated with major depressive disorder mdd. Rapid and accurate haplotype phasing and missingdata inference for wholegenome association studies by use of localized haplotype clustering. Background diffculty in detecting rare variants is one of the problems in conventional genome wide association studies gwas. As marker density increases, the chance that a single snp will be in strong ld with a qtl increases. Haplotype analyses linkage disequilibrium assessment diseasegene discovery genetic demography chromosomal evolution studies why haplotypes haplotypes are more powerful discriminators between cases and controls in disease association studies use of.
When this was done, several studies in rapid succession identified a strong pattern of variation that soon received the name haplotype blocks. Genomewide association studies using haplotypes and individual. In particular, we consider the em and wem algorithm as two representatives of haplotypebased approaches because of their easy implementation. Significant genetic association may be interpreted as either 1 direct association, in which the genotyped snp is the true causal variant conferring disease susceptibility. Martin bishop 0 inserm, umr s 525 and universite pierre et marie curieparis6, umr s 525, paris, france summary. We choose the casecontrol design as an illustrative example since it is probably the most commonly used in association studies. Mander mrc biostatistics unit, cambridge, uk adrian. The haplotype analysis approach, although much more complicated and requiring significantly larger study populations than the traditional single gene association studies, appears to be more logical and comprehensive, and thus stands a better chance of success in achieving the goals set forth by this type of research. Comparison of haplotypebased and treebased snp imputation. Apr 18, 2019 background diffculty in detecting rare variants is one of the problems in conventional genome wide association studies gwas.
Haplotype methods for populationbased association studies. A high resolution hla and snp haplotype map for disease. This paper describes how to use the command hapipf and introduces the command profhap written for stata that analyzes populationbased genetic data. Haplotype uncertainty in association studies request pdf. Factors affecting the power of haplotype markers in. Daf, derived allele frequency gwas, genomewide association study. Snp and haplotypebased genomewide association studies for. Haplotype analysis in population genetics and association studies. A method for using haplotype trees in phenotypegenotype association studies alan r. Multinomial logistic regression approach to haplotype. In each block, a small fraction of singlenucleotide polymorphisms snps, referred to as tag snps, can be used to distinguish a large fraction of the haplotypes. A haplotypeage interaction effect is also identified. A genomewide haplotype association study for mdd was undertaken utilising a familybased population cohort, generation scotland.
The use of haplotype information in casecontrol studies is an area of focus for the research on the association between phenotypes and genetic polymorphisms. Pdf several studies of haplotype structures in the human genome in various populations have been published recently. Haplotypebased genome wide association study using a novel. Haplotype analysis in populationbased association studies a. Pdf importance of haplotype analysis in association. Candidate genes, association studies and haplotype analysis. In addition to the command line interface, a graphical java interface is now proposed allowing one to run thesias in a userfriendly manner. Locus haplotype locus window name haplotype haplotype identifer f frequency in sample founders testing for haplotypebased casecontrol and quantitative trait association in a populationbased sample of unrelated individuals, casecontrol and quantitative traits can be analysed for haplotype associations, using the option, for example. The haplotype analysis approach, although much more complicated and requiring significantly larger study populations than the traditional single gene association studies, appears to be more logical and comprehensive, and thus stands a better chance of success in. Principles of haplotype mapping and potential applications to. For these studies, association can be linkage disequilibrium within a set of loci or allelichaplotype association with disease status. Snps, imputation and haplotypes nilanjan chatterjee, yihau chen, sheng luo and raymond j. This approach exploits the existing genetic diversity and historical recombination events captured within a population to examine the degree of association between thousands or millions of snps with a trait of interest varshney and tuberosa, 2007.
Confidence intervals for odds ratios are calculated with or without adjustment for possible factors that are confounding the relationship. Locus haplotype locus window name haplotype haplotype identifer f frequency in sample founders testing for haplotype based casecontrol and quantitative trait association in a populationbased sample of unrelated individuals, casecontrol and quantitative traits can be analysed for haplotype associations, using the option, for example. Haplotypebased association analysis in cohort studies of. In addition to the command line interface, a graphical java interface is now proposed allowing one to run thesias in a. In addition, we may accommodate hardyweinberg disequilibrium as in lin et al. Genomewide association studies using genotype data have had limited success in the identification of variants associated with major depressive disorder mdd. Powerful testing via hierarchical linkage disequilibrium in. Thesias testing haplotype effects in association studies is a popular software for. This made human geneticists want to consider only snps above some frequency threshold. Likelihoodbased inference on haplotype effects in genetic association studies d. Box 1 rationale for association studies population association studies compare unrelated individuals, but unrelated actually means that relationships are unknown and. However, with improvements in the computational efficiency of phasing and haplotype analysis software, genomewide haplotypebased association studies are becoming increasingly realistic and show great promise for discovering novel loci contributing effects to complex human traits. The statistical properties of the models were investigated through simulation studies and its usefulness and utilization validated by analyzing the genetic association of sarcoidosis from a human genetics project.
Test of association between haplotypes and phenotypes in case. A fast approach to boosting haplotype association analyses in genomewide association studies xiang wan, can yang, qiang yang, hongyu zhao, and weichuan yu abstractgenomewide association study gwas has been successful in identifying genetic variants that are associated with complex human diseases. Bmc genetics snp and haplotypebased genomewide association studies for growth, carcass, and meat quality traits in a duroc multigenerational population shuji sato 0 1 yoshinobu uemoto 0 1 takashi kikuchi 1 sachiko egawa 3 kimiko kohira 1 tomomi saito 1 hironori sakuma 1 satoshi miyashita 3 shinji arata 3 takatoshi kojima 1 keiichi suzuki 2 0 equal contributors 1 national. Factors affecting the power of haplotype markers in association. Haplotype analysis improved evidence for candidate genes for.
Genetic association studies zin contrast to linkage studies, association studies can identify variants with relatively small individual contributions to disease risk zhowever, they require detailed measurement of genetic variation and there are 10,000,000 catalogued genetic variants zuntil recently, studies limited to candidate genes or regions. Ld metric, to set the xaxis to equal spacing or to use the physical map of markers, and to specify plot. Fugue em based haplotype estimation and association tests in unrelated and nuclear families. In a recent gwas, we found that none of the known candidate genes for intramuscular fat imf had been identified. The population associations between haplotypes and disease phenotypes provide critical information about the genetic basis of complex human diseases. Comparison of methods and empirical evaluation of the literature. Box 1 rationale for association studies population association studies compare unrelated individuals, but unrelated actually means that relationships are unknown and presumed to be distant. Genomewide haplotypebased association analysis of major. More recently, association studies using diplotypes haplotype pairs on homologous chromosomes have become increasingly common.
The main features of the package include options to display a linkage disequilibrium ld plot below the pvalue plot using either the r 2 or d. Please view the pdf by using the full text pdf link under view to the left. Haplotype based association analysis in cohort studies of unrelated individuals d. T he framework required for completing a genetic study has been developed and most. However, with improvements in the computational efficiency of phasing and haplotype analysis software, genomewide haplotype based association studies are becoming increasingly realistic and show great promise for discovering novel loci contributing effects to complex human traits. A tutorial on statistical methods for population association.
May 21, 2019 an integrated gwas procedure, considering singlelocus and multilocus gwas approaches jointly, may improve the capacity of association studies to detect key qtls and to provide a more complete picture of the genetic architecture of complex traits in barley. Hplus 12 a software package for imputation and testing of haplotypes in association studies using a modified method that incorporates the expectationmaximization algorithm and a bayesian method known as progressive ligation. Haplotype analysis in populationbased association studies. Thus, the current study was performed to construct the haplotype structure in the bovine genome and to detect the relevant genes genuinely.
Sing department of biology, washington university, st. A tutorial on statistical methods for population association studies. A genomewide haplotype association analysis of major. Pdf haplotype analysis in population genetics and association. Detecting haplotype effects in genomewide association studies. These tag snps can potentially be extremely useful for.
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