Will haplotype maps be useful for finding genes?

Oord, Edwin J. C. G. van den; Neale, Benjamin M.

doi:10.1038/sj.mp.4001449

Cited by 35 publications

(19 citation statements)

References 58 publications

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“…In contrast, the HapMap was designed to identify more common disease-causing variants based upon the "common disease, common variant" hypothesis, which suggests that genetic influences on many common diseases are attributable to a limited number of allelic variants (one or a few at each major disease locus) that are present in more than 1%-5% of the population (10)(11)(12). Evidence supporting this hypothesis was modest at the outset of the HapMap Project, and reliance on the hypothesis sparked considerable controversy (13)(14)(15)(16). Understanding how that controversy played out and was ultimately resolved by the remarkable success of the genetic association studies enabled by the HapMap requires an understanding of genetic variation, population genetics, and the evolution of the HapMap itself.…”

Section: Genetic Influences On Common Diseasesmentioning

confidence: 99%

A HapMap harvest of insights into the genetics of common disease

Manolio

Brooks²,

Collins³

2008

J. Clin. Invest.

805

630

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The International HapMap Project was designed to create a genome-wide database of patterns of human genetic variation, with the expectation that these patterns would be useful for genetic association studies of common diseases. This expectation has been amply fulfilled with just the initial output of genome-wide association studies, identifying nearly 100 loci for nearly 40 common diseases and traits. These associations provided new insights into pathophysiology, suggesting previously unsuspected etiologic pathways for common diseases that will be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. In addition, HapMap-based discoveries have shed new light on the impact of evolutionary pressures on the human genome, suggesting multiple loci important for adapting to disease-causing pathogens and new environments. In this review we examine the origin, development, and current status of the HapMap; its prospects for continued evolution; and its current and potential future impact on biomedical science.Nonstandard abbreviations used: GWA, genome-wide association; LD, linkage disequilibrium; OR, odds ratio. approach would be very expensive and would not capture rarer variants or structural variants (such as insertions, deletions, and inversions) that are not identified by genotyping of SNPs. However, the pattern of association among SNPs in the genome suggests a potential shortcut, based on haplotypes and linkage disequilibrium (LD). A haplotype is the combined set of alleles at a number of closely spaced sites on a single chromosome. Nearby SNP alleles tend to be associated with each other, or inherited together more often than expected by chance, because most arise through mutational events that each occur once on an ancestral haplotype background and are inherited with that background, rather than arising multiple times de novo on different backgrounds (18). This is because for most SNPs the rate of mutation, or novel SNP generation, is relatively low (roughly 10 -8 per site per generation, or 30 new variants per haploid gamete), as are the rate of recombination occurring with each meiosis and the number of generations (roughly 10 4 ) between currently living individuals and their most recent common ancestor (3). Each new allele is initially associated with the other allelic variants present on the particular stretch of ancestral DNA on which it arose, and these associations are only slowly broken down over time by recombination between SNPs and generation of new variants ( Figure 2) (3). Two polymorphic sites are said to be in LD when their specific alleles are correlated in a population. High LD means that the SNP alleles are almost always inherited together; information about GlossaryAllele, an alternative form of a gene or SNP, or another type of variant Biallelic, having only two possible alleles in a variant, typically a SNP Confidence interval, the range of values surrounding a point estimate, such as an OR, within which the true value is be...

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Section: Genetic Influences On Common Diseasesmentioning

confidence: 99%

A HapMap harvest of insights into the genetics of common disease

Manolio

Brooks²,

Collins³

2008

J. Clin. Invest.

805

630

View full text Add to dashboard Cite

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“…It is unlikely that blocks represent discrete entities with clear cut boundaries since the size of conserved ancestral haplotypes in a given region may differ. 46 Variability in size of conserved haplotypes is clearly recognised in the MHC, 28 and long-range LD beyond the confines of blocks has been observed in this region. 47 As a consequence, the boundaries of haplotype blocks are likely to depend on the relative frequency of the various ancestral and recombinant haplotypes.…”

Section: Hla Haplotype Specific Ld In the Xmhcmentioning

confidence: 99%

“…47 As a consequence, the boundaries of haplotype blocks are likely to depend on the relative frequency of the various ancestral and recombinant haplotypes. 46 This may have practical implications, as a disease association sometimes is restricted to a defined LD block. Caution should be taken when employing blocks in fine mapping as the block boundaries are not fixed and will shift depending on various parameters including the HLA background.…”

Section: Hla Haplotype Specific Ld In the Xmhcmentioning

confidence: 99%

Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB103 and DRB104 haplotypes

et al. 2006

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First generation linkage disequilibrium (LD) and haplotype maps of the human major histocompatibility complex (MHC) have been generated in order to aid the unraveling of the numerous disease predisposing genes in this region by offering a first set of haplotype tagSNPs. Several parameters, like the population studied, the marker map used, the density of polymorphisms and the applied algorithm, are influencing the appearance of haplotype blocks and selection of tags. The MHC comprises a limited number of ancestral, conserved haplotypes. We address the impact of the underlying HLA haplotypes on the LD patterns, haplotype blocks and tag selection throughout the entire extended MHC (xMHC) by studying DR-DQ haplotypes, mainly those carrying DRB1*03 and DRB1*04 alleles. We observed significantly different degree and extent of LD calculated on different HLA backgrounds, as well as variation in the size and boundaries of the defined haplotype and tags selected. Our results demonstrate that the underlying ancestral HLA haplotypic architecture is yet another parameter to take into consideration when constructing LD maps of the xMHC. This may be essential for mapping of disease susceptibility genes since many diseases are associated with and map on particular HLA haplotypes.

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“…'htSNPs' were then selected within each 'LD block' for 90% haplotype coverage using SNPtagger software (Ke and Cardon, 2003). This strategy for association analyses after initial LD mapping and 'htSNPs' selection is considered to be reasonable on the basis of descriptions given in other papers (Kamatani et al, 2004;van den Oord and Neale, 2004).…”

Section: Selection Of 'Htsnps'mentioning

confidence: 99%

Positive Association of the Serotonin 5-HT7 Receptor Gene with Schizophrenia in a Japanese Population

Ikeda

Iwata

Kitajima

et al. 2005

Neuropsychopharmacol

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Several lines of evidence suggest that abnormalities in the serotonin system may be related to the pathophysiology of schizophrenia. The 5-HT 7 receptor is considered to be a possible schizophrenia-susceptibility factor, based on findings from binding, animal, postmortem, and genomewide linkage studies. In this study, we conducted linkage disequilibrium (LD) mapping of the human 5-HT 7 receptor gene (HTR7) and selected four 'haplotype-tagging (ht) SNPs'. Using these four htSNPs, we then conducted an LD case-control association analysis in 383 Japanese schizophrenia patients and 351 controls. Two htSNPs (SNP2 and SNP5) and haplotypes were found to be associated with schizophrenia. A promoter SNP (SNP2) was further assessed in a dual-luciferase reporter assay, but it was not found to have any functional relevance. Although we failed to find an actual susceptibility variant that could modify the function of HTR7, our results support the supposition that HTR7 is a susceptibility gene for schizophrenia in this ethnic group.

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Will haplotype maps be useful for finding genes?

Cited by 35 publications

References 58 publications

A HapMap harvest of insights into the genetics of common disease

A HapMap harvest of insights into the genetics of common disease

Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB103 and DRB104 haplotypes

Positive Association of the Serotonin 5-HT7 Receptor Gene with Schizophrenia in a Japanese Population

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Will haplotype maps be useful for finding genes?

Cited by 35 publications

References 58 publications

A HapMap harvest of insights into the genetics of common disease

A HapMap harvest of insights into the genetics of common disease

Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB1*03 and DRB1*04 haplotypes

Positive Association of the Serotonin 5-HT7 Receptor Gene with Schizophrenia in a Japanese Population

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Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB103 and DRB104 haplotypes