Mapping complex disease loci in whole-genome association studies
NaturePublished 1 May 2004
Christopher S. Carlson, Michael A. Eberle, Leonid Kruglyak, Deborah A. Nickerson
Citations625
SJR quartileQ1
SJR score18.29
SNIP10.16
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TL;DR
Association studies of this type have good prospects for dissecting the genetics of common disease, but they currently face a number of challenges, including problems with multiple testing and study design, definition of intermediate phenotypes and interaction between polymorphisms.
Abstract
Identification of the genetic polymorphisms that contribute to susceptibility for common diseases such as type 2 diabetes and schizophrenia will aid in the development of diagnostics and therapeutics. Previous studies have focused on the technique of genetic linkage, but new technologies and experimental resources make whole-genome association studies more feasible. Association studies of this type have good prospects for dissecting the genetics of common disease, but they currently face a number of challenges, including problems with multiple testing and study design, definition of intermediate phenotypes and interaction between polymorphisms.
Keywords
Biochemistry, Genetics and Molecular Biology
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The Gene Expression Omnibus (GEO) project was initiated in response to the growing demand for a public repository for high-throughput gene expression data and provides a flexible and open design that facilitates submission, storage and retrieval of heterogeneous data sets from high-power gene expression and genomic hybridization experiments.
Proceedings of the National Academy of SciencesStatistical significance for genomewide studies
10,072 Citations2003John D. Storey, Robert Tibshirani
This work proposes an approach to measuring statistical significance in genomewide studies based on the concept of the false discovery rate, which offers a sensible balance between the number of true and false positives that is automatically calibrated and easily interpreted.
NatureThe International HapMap Project
6,170 Citations2003Richard A. Gibbs, John W. Belmont +181 more
The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance the ability to choose targets for therapeutic intervention.
ScienceThe Structure of Haplotype Blocks in the Human Genome
5,921 Citations2002Stacey Gabriel, S. F. Schaffner +16 more
It is shown that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed.
ScienceThe Future of Genetic Studies of Complex Human Diseases
5,384 Citations1996Neil Risch, Kathleen R. Merikangas
In their Perspective, Risch and Merikangas propose that the power of the human genome project with association studies, a method for determining the basis of a genetic disease, can best accomplish the identification of the genetic basis of complex human diseases such as schizophrenia and diabetes.
Nature GeneticsGenetic dissection of complex traits: guidelines for interpreting and reporting linkage results
5,292 Citations1995Eric S. Lander, Leonid Kruglyak
Specific standards designed to maintain rigor while also promoting communication are proposed for the interpretation of linkage results in genetic studies under way for many complex traits.
Nucleic Acids ResearchThe Gene Ontology (GO) database and informatics resource
4,722 Citations2003Midori A. Harris
The Gene Ontology (GO) project provides structured, controlled vocabularies and classifications that cover several domains of molecular and cellular biology and are freely available for community use in the annotation of genes, gene products and sequences.
NatureA map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms
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This high-density SNP map provides a public resource for defining haplotype variation across the genome, and should help to identify biomedically important genes for diagnosis and therapy.
Nature GeneticsMeta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease
1,904 Citations2003Kirk E. Lohmueller, Celeste Leigh Pearce +3 more
It is concluded that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.
NatureA vision for the future of genomics research
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Nature GeneticsCharacterization of single-nucleotide polymorphisms in coding regions of human genes
1,554 Citations1999Michele Cargill, David Altshuler +15 more
Nature GeneticsDiscovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease
1,507 Citations2003David Botstein, Neil Risch
The distribution of types of mutation in mendelian disease genes argues for serious consideration of the early application of a genomic-scale sequence-based approach to association studies and against complete reliance on a positional cloning approach based on a map of anonymous single nucleotide polymorphism haplotypes.
Nature GeneticsProspects for whole-genome linkage disequilibrium mapping of common disease genes
1,428 Citations1999Leonid Kruglyak
The American Journal of Human GeneticsLinkage Disequilibrium in Humans: Models and Data
1,330 Citations2001Jonathan K. Pritchard, Molly Przeworski
This review describes recent empirical and theoretical work on the extent of linkage disequilibrium in the human genome, comparing the predictions of simple population-genetic models to available data and some implications that the emerging patterns of LD have for association-mapping strategies.
Genome biologyGoMiner: a resource for biological interpretation of genomic and proteomic data
1,209 Citations2003Barry R. Zeebèrg, Weimin Feng +12 more
GoMiner, a program package that organizes lists of 'interesting' genes for biological interpretation in the context of the Gene Ontology, provides quantitative and statistical output files and two useful visualizations.
Trends in GeneticsOn the allelic spectrum of human disease
1,188 Citations2001David Reich, Eric S. Lander
Human disease genes show enormous variation in their allelic spectra; that is, in the number and population frequency of the disease-predisposing alleles at the loci, so the theory does a reasonable job for diseases where the genetic etiology is well understood.
Nature GeneticsHaplotype tagging for the identification of common disease genes
1,178 Citations2001Gillian C.L. Johnson, Laura Esposito +19 more
This work shows how knowledge of the common haplotypes and the SNPs that tag them can be used to explain the often complex patterns of LD between adjacent markers and provide key fine-mapping data within regions of strong LD.
ScienceBlocks of Limited Haplotype Diversity Revealed by High-Resolution Scanning of Human Chromosome 21
1,150 Citations2001Nila Patil, Anthony Berno +20 more
High-density oligonucleotide arrays are used in combination with somatic cell genetics to identify a large fraction of all common human chromosome 21 SNPs and to directly observe the haplotype structure defined by these SNPs.
Bioinformatics<i>VISTA</i> : visualizing global DNA sequence alignments of arbitrary length
1,066 Citations2000Chris Mayor, Michael Brudno +6 more
Vista is a program for visualizing global DNA sequence alignments of arbitrary length that has a clean output, allowing for easy identification of similarity, and is easily configurable, enabling the visualization of alignments at different levels of resolution.
ScienceVariations on a Theme: Cataloging Human DNA Sequence Variation
1,053 Citations1997Francis S. Collins, Mark S. Guyer +1 more
This Policy Forum, the authors call for a publicly supported effort to discover a large number of SNPs and to place the information in public databases.
GenomicsA Comparison of Linkage Disequilibrium Measures for Fine-Scale Mapping
1,052 Citations1995Bernie Devlin, Neil Risch
This work investigates the simple mapping properties of five disequ equilibrium measures, the correlation coefficient delta, Lewontin's D', the robust formulation of the population attributable risk delta, Yule's Q, and Kaplan and Weir's proportional difference d under the assumption of initial complete disequilibrium between disease and marker loci, and indicates that delta is a superior measure for fine mapping.
Nature GeneticsPatterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis
1,013 Citations1999Marc K. Halushka, Jian-Bing Fan +7 more
The degree of nucleotide polymorphism across these human genes, and orthologous great ape sequences, is highly variable and is correlated with the effects of functional conservation on gene sequences.
ScienceHaplotype Variation and Linkage Disequilibrium in 313 Human Genes
875 Citations2001Jonathan Stephens, Julie A. Schneider +26 more
Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency.
Nature GeneticsThe molecular basis of the human serum paraoxonase activity polymorphism
840 Citations1993Richard Humbert, David A. Adler +4 more
It is demonstrated that arginine at position 192 specifies high activity PON whereas a glutamine specifies the low activity variant, and that PON maps to chromosome 7q21–22, proximal to the cystic fibrosis gene, in agreement with previous genetic linkage studies.
Genome ResearchA DNA Polymorphism Discovery Resource for Research on Human Genetic Variation: Table 1.
830 Citations1998Francis S. Collins, Lisa Brooks +1 more
A large number of mapped SNPs will be valuable as markers throughout the genome for finding SNPs that do affect gene function, as linkage disequilibrium over tens to hundreds of kilobases is expected to be found in many regions of the human genome.
Nucleic Acids ResearchWormBase: a multi-species resource for nematode biology and genomics
701 Citations2003Todd Harris
The nearly complete genomic sequence and comparative analyses of the closely related species Caenorhabditis briggsae have been integrated into WormBase, including gene predictions, ortholog assignments and a new synteny viewer to display the relationships between the two species.
NatureComparative analyses of multi-species sequences from targeted genomic regions
663 Citations2003James W. Thomas, Jeff Touchman +69 more
The generation and analysis of over 12 megabases of sequence from 12 species, all derived from the genomic region orthologous to a segment of about 1.8 Mb on human chromosome 7 containing ten genes, show conservation reflecting both functional constraints and the neutral mutational events that shaped this genomic region.
Nature Reviews GeneticsThe complex interplay among factors that influence allelic association
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This work considers how the effect size of the susceptibility locus, the frequency of the disease allele(s), the Frequency of the marker allele (s) that are correlated with the disease alleles and the extent of linkage disequilibrium together influence genetic association studies.
Nature Reviews GeneticsDNA Pooling: a tool for large-scale association studies
556 Citations2002Pak C. Sham, Joel S. Bader +3 more
Recent developments in quantitative genotyping assays and in the design and analysis of pooling studies are discussed.
SciencePhylogenetic Shadowing of Primate Sequences to Find Functional Regions of the Human Genome
526 Citations2003Dario Boffelli, Jon McAuliffe +5 more
The utility of intraprimate sequence comparisons to discover common mammalian as well as primate-specific functional elements in the human genome, which are unattainable through the evaluation of more evolutionarily distant species are demonstrated.
PubMedMolecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A or B allozymes.
485 Citations1993S. Adkins, K Gan +2 more
Pedigree analysis showed both polymorphisms to be inherited in the expected Mendelian manner and confirmed that only the 191 polymorphism showed concordance with the serum paraoxonase/arylesterase phenotypes.
Statistics in MedicineNon‐hierarchical logistic models and case‐only designs for assessing susceptibility in population‐based case‐control studies
482 Citations1994Walter W. Piegorsch, Clarice R. Weinberg +1 more
If the exposure and genetic categories occur independently and the disease is rare, then analyses based only on cases are valid, and offer better precision for estimating gene-environment interactions than those based on the full data.
The LancetSynergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction
420 Citations1994Laurence Tiret, Pierre Ducimetière +10 more
A significant interaction between ACE and AGT1R gene polymorphisms is found; the odds ratio for myocardial infarction associated with the ACE DD genotype was 1.05, and these findings, if confirmed, could have clinical implications for the prevention and treatment of coronary heart disease.
American Journal of EpidemiologyNontraditional Epidemiologic Approaches in the Analysis of Gene Environment Interaction: Case-Control Studies with No Controls!
418 Citations1996Muin J. Khoury, W. Dana Flanders
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407 Citations2003Daniel O. Stram, Christopher A. Haiman +5 more
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368 Citations1998Neil Risch, Jun Teng
It is demonstrated that for sibships with parents, only the parents require individual genotyping to derive the TDT statistic, whereas all the offspring can be pooled, which can potentially lead to considerable savings in genotypes, especially for multiplex sibship.
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The results presented here indicate that the L55M effect of lowered activity is not due to the amino acid change but is, rather, largely due to linkage disequilibrium with the -108 regulatory-region polymorphism.
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315 Citations2003Anna Rocchi, Silvia Pellegrini +2 more
It is concluded that a better understanding of the complex aetiology that underlies AD may be achieved likely through a multidisciplinary approach that combines clinical and neurophysiological characterization of AD subtypes and in vivo functional brain imaging studies with molecular investigations of genetic components.
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The results support the benefit of a “level crossing” approach that includes intervening phenotypes in the study of complexly inherited disease.
The American Journal of Human GeneticsHaplotype Block Structure and Its Applications to Association Studies: Power and Study Designs
268 Citations2002Kui Zhang, Peter Calabrese +2 more
This study develops a simulation study to quantitatively assess the power loss for a variety of study designs, including case-control designs and case-parental control designs, and indicates that haplotype-based analysis can be much more powerful than marker-by-marker analysis.
International Archives of Occupational and Environmental HealthUrinary cotinine as a tobacco-smoke exposure index: a minireview
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This minireview considers major problems encountered in the establishment of threshold values that can be used to distinguish not only smokers from nonsmoker but also nonsmokers exposed or not exposed to environmental tobacco smoke (ETS).
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231 Citations2003Scott Schwartz
The MultiPipMaker server is described, which aligns multiple, long genomic DNA sequences quickly and with good sensitivity, and the use of the alignments confirms the phylogenetic inference that horses are more closely related to cats than to cows.
PubMedStatistical analysis of molecular epidemiology studies employing case-series.
215 Citations1994Colin B. Begg, Zuo‐Feng Zhang
The case-series approach represents an efficient and valid approach for evaluating gene-environment associations, especially in referral centers where it is difficult to identify a valid control group.
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A java-based program, SNPtagger, is described, which screens for minimal sets of SNP markers to represent given haplotypes according to various user requirements and offers several options for inclusion/exclusion of specific markers and presents alternative panels for final selection.
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128 Citations1996Michael R. Kosorok, WEN-HSIANG WEI +1 more
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122 Citations2004Ileana M. Cristea, Simon J. Gaskell +1 more
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119 Citations2003
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107 Citations2002Karen L. Mohlke, Michael R. Erdos +7 more
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98 Citations1997Stephen Sawcer, Hywel B. Jones +5 more
The main conclusion is that, for the particular set of families and markers used in the screen, an MLS of 3.2 carries a genome‐wide significance of 5% (that is, there is a 5% probability of observing at least one false hit, above this threshold in a complete genome screen), somewhat reassuring, in view of the very large sample sizes that would be necessary to achieve adequate power to detect linkage at the more stringent threshold.
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95 Citations2003Stefan Kammerer, Lora Hamuro +9 more
This study suggests that alterations in PKA-RIα subcellular localization caused by variation in d-AKAP2 may have a negative health prognosis in the aging population, which may be related to cardiac dysfunction.
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75 Citations2003Allison E Bonner, W J Lemon +1 more
Many of the genes involved in lung development are either known oncogenes or tumour suppressor genes altered in lung cancer, such as Cyr61, Rassf1a, and Dutt1/Robo1, or putative lung cancer genes.
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紀要PCR-based screening for cystic fibrosis carrier mutations in an ethnically diverse pregnant population.
66 Citations1997W W Grody, Christine Dunkel‐Schetter +7 more
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64 Citations2003Yaning Yang, Jingshan Zhang +5 more
A method for obtaining maximum likelihood estimates of haplotype frequencies for different pool sizes is developed, the accuracy of these estimates are assessed, and it is shown that pooling DNA samples is efficient in estimating haplotypes frequencies.
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60 Citations2002Nicholas J. Schork
An approach to assessment of the power and sample-size requirements of genetic case-control association study designs that makes use of empirically derived estimates of the distributions of important parameters often assumed to take on arbitrary values is considered.
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Embryos that have combined MTHFR 677TT and TC 776CG or 776GG genotypes; genotypes that individually are associated with impaired homocysteine metabolism in adults, are at increased risk for spontaneous abortion compared with embryos that have only one of these genotypes.
Epidemiologic ReviewsEvolving Methods in Genetic Epidemiology. II. Genetic Linkage from an Epidemiologic Perspective
35 Citations1997Neil Risch
Genes are risk factors for disease, and, thus, their identification and determination of their population frequency have direct relevance to understanding disease etiology and to developing appropriate public health measures.
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24 Citations2002Marshall Alan Permutt, J. Wasson +6 more
The SNP association study showed that SNP rs2664537 in the TIX1 gene had a significant P value of 0.035, but the finding did not replicate in an additional case pool, and the limits to this type of association study are discussed.
Annals of the Rheumatic DiseasesHLA class II DR, DQ, and DP restriction fragment length polymorphisms in rheumatoid arthritis.
5 Citations1989W. M. Howell, Philip R. Evans +3 more
HLA class II restriction fragment length polymorphisms were studied in 43 individuals with established seropositive rheumatoid arthritis and in a group of healthy controls to indicate a role for DQ beta genetic variation in the aetiology of RA.