Showing papers by "David Altshuler published in 2003"
TL;DR: An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.
Abstract: DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.
7,997 citations
Baylor College of Medicine1, Chinese Academy of Sciences2, Chinese National Human Genome Center3, University of Hong Kong4, The Chinese University of Hong Kong5, Hong Kong University of Science and Technology6, Illumina7, McGill University8, Washington University in St. Louis9, University of California, San Francisco10, Wellcome Trust Sanger Institute11, Beijing Normal University12, Health Sciences University of Hokkaido13, Shinshu University14, University of Tsukuba15, Howard University16, University of Ibadan17, Case Western Reserve University18, University of Utah19, Cold Spring Harbor Laboratory20, Johns Hopkins University21, University of Oxford22, North Carolina State University23, National Institutes of Health24, Massachusetts Institute of Technology25, Chinese Academy of Social Sciences26, Kyoto University27, Nagasaki University28, Wellcome Trust29, Genome Canada30, Foundation for the National Institutes of Health31, University of Maryland, Baltimore32, Vanderbilt University33, Stanford University34, University of California, Berkeley35, New York University36, University of Oklahoma37, University of New Mexico38, Université de Montréal39, University of California, Los Angeles40, University of Michigan41, University of Wisconsin-Madison42, London School of Economics and Political Science43, Genetic Alliance44, GlaxoSmithKline45, University of Washington46, Harvard University47, University of Chicago48, Fred Hutchinson Cancer Research Center49, University of Tokyo50
TL;DR: 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.
Abstract: The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.
5,926 citations
TL;DR: An approach for picking haplotype-tagging single nucleotide polymorphisms (htSNPs) that is presently being taken in two large nested case-control studies within a multiethnic cohort (MEC), which are engaged in a search for associations between risk of prostate and breast cancer and common genetic variations in candidate genes.
Abstract: We describe an approach for picking haplotype-tagging single nucleotide polymorphisms (htSNPs) that is presently being taken in two large nested case-control studies within a multiethnic cohort (MEC),
420 citations
TL;DR: The lessons learned from an extensive body of evidence on the division of diabetes into different subtypes based on clinical phenotype are used to illustrate general implications for the genetic analysis of complex traits.
Abstract: Diabetes encompasses a heterogeneous group of diseases, each with a substantial genetic component We review the division of diabetes into different subtypes based on clinical phenotype, the fruitful pursuit of genes underlying monogenic forms of the disease, the successes and drawbacks of whole-genome linkage scans in type 1 and type 2 diabetes, and the recent identification of several diabetes genes by large association studies We use the lessons learned from this extensive body of evidence to illustrate general implications for the genetic analysis of complex traits
326 citations
TL;DR: The goal of this paper is to outline the issues involved in choosing a method of estimating haplotype-specific risk estimates for such data that is technically appropriate and yet attractive to epidemiologists who are already comfortable with odds ratios and logistic regression.
Abstract: The US National Cancer Institute has recently sponsored the formation of a Cohort Consortium (http://2002.cancer.gov/scpgenes.htm) to facilitate the pooling of data on very large numbers of people, co
254 citations
TL;DR: To address the quality and completeness of single-nucleotide polymorphism (SNP) databases, 173 kb was resequenced in 150 chromosomes of west African and European ancestry and over 88% of SNPs in the public and Celera databases were confirmed in independent resequencing.
Abstract: To address the quality and completeness of single-nucleotide polymorphism (SNP) databases, we resequenced 173 kb (spanning 17 loci) in 150 chromosomes of west African and European ancestry. Over 88% of SNPs in the public (TSC and BAC overlap) and Celera databases were confirmed in independent resequencing. Approximately 45% of all human heterozygosity is attributable to SNPs already available from the two databases, and of SNPs with minor-allele frequencies >10%, more than half are represented.
209 citations
TL;DR: The hypothesis that women with the long-range CYP19 haplotype 2b-3c may be carriers of a predisposing breast cancer susceptibility allele is suggested.
Abstract: The CYP19 gene encodes for aromatase (P450arom), a key steroidogenic enzyme that catalyzes the final step of estrogen biosynthesis. Apart from rare mutations in CYP19 which result in severe phenotypes associated with estrogen insufficiency, little is known about whether common variation in CYP19 is associated with risk of hormone-related diseases. In this study, we employed a haplotype-based approach to search for common disease-associated variants in this candidate breast cancer susceptibility gene among African-American, Hawaiian, Japanese, Latina and White women in the Multiethnic Cohort Study (MEC). We utilized 74 densely spaced single-nucleotide polymorphisms (SNPs) (one every approximately 2.6 kb) spanning 189.4 kb of the CYP19 locus to characterize linkage disequilibrium (LD) and haplotype patterns among 69-70 individuals from each ethnic population. We detected four regions of strong LD (blocks 1-4) that were quite closely conserved across populations. Within each block there was a limited diversity of common haplotypes (5 to 10 with a frequency >/=5%) and most haplotypes were observed to be shared across populations. Twenty-five haplotype-tagging SNPs (htSNPs) were selected to predict the common haplotypes with high probability (average Rh2=0.92) and genotyped in a breast cancer case-control study in the MEC (cases, n=1355; controls, n=2580). We first performed global tests for differences in risk according to the common haplotypes and observed significant haplotype-effects in block 2 [P=0.01; haplotypes 2b (OR=1.23; 95% CI, 1.07-1.40), 2d (OR=1.28; 95% CI, 1.01-1.62)]. We also found a common long-range haplotype comprised of block-specific haplotypes 2b and 3c to be associated with increased risk of breast cancer (haplotype 2b-3c: OR=1.31; 95% CI, 1.11-1.54). Our findings suggest the hypothesis that women with the long-range CYP19 haplotype 2b-3c may be carriers of a predisposing breast cancer susceptibility allele.
143 citations
TL;DR: The results of this study provide further support for an inverse association between the PPARgamma variant 12Ala allele and risk of type 2 diabetes.
Abstract: OBJECTIVE —To determine whether the Pro12Ala polymorphism in the PPAR γ gene was associated with risk of type 2 diabetes in the Nurses’ Health Study. RESEARCH DESIGN AND METHODS —The study was a nested case-control study of 387 incident cases of type 2 diabetes and 771 matching control subjects nested within the Nurses’ Health Study, a prospective cohort study. Association between PPAR γ genotype and incident type 2 diabetes was estimated using logistic regression. RESULTS —Carriers of the PPAR γ variant 12Ala allele had reduced risk of type 2 diabetes compared with noncarriers. Unadjusted and adjusted odds ratios of type 2 diabetes were 0.74 (95% CI 0.55–1.00) and 0.72 (0.52–0.99), respectively. CONCLUSIONS —The results of this study provide further support for an inverse association between the PPAR γ variant 12Ala allele and risk of type 2 diabetes.
67 citations
TL;DR: Understanding the methods of population-based genetic investigation and the patterns of human genome variation will enable stroke physicians to follow these future developments.
Abstract: Background— Technological progress spurred by the Human Genome Project is accelerating the pace of genetic studies of common diseases, including stroke. Stroke clinicians will soon need to interpret increasingly complex genetic studies. Summary of Review— Linkage analysis and epidemiological association are 2 fundamental methods of identifying gene variants affecting common diseases such as stroke. Combining these methods with advanced molecular genetic techniques, 3 recently published studies have made important contributions to the genetics of common vascular diseases: identification of the location of a gene for stroke on chromosome 5q12 and identification of gene variants that may increase risk of myocardial infarction. Driven by genomic technology, future studies will be increasingly comprehensive and systematic in their assessment of the contribution of genetics to the clinical course of stroke. The scale and complexity of such studies will require large-scale collaboration among stroke physicians, ...
37 citations
TL;DR: One lineage, found only among the Japanese group in this study, was associated with a statistically significant predisposition to prostate cancer, suggesting that a Y chromosomal factor contributes significantly to the development of prostate cancer in Japanese men.
Abstract: Background: A Y chromosomal role in prostate cancer has previously been suggested by both cytogenetic findings and patterns of Y chromosomal gene expression. We took advantage of the well established and stable phylogeny of the non-recombining segment of the Y chromosome to investigate the association between Y chromosomal DNA variation and prostate cancer risk.
Methods: We examined the distribution of 116 Y lineages in 930 prostate cancer cases and 1208 controls from four ethnic groups from a cohort study in Hawaii and California.
Results: One lineage, found only among the Japanese group in our study, was associated with a statistically significant predisposition to prostate cancer (odds ratio (OR) = 1.63; 95% confidence interval (CI) 1.07 to 2.47), and, in particular, to high severity disease in younger individuals (OR = 3.89; 95% CI 1.34 to 11.31).
Conclusions: This finding suggests that a Y chromosomal factor contributes significantly to the development of prostate cancer in Japanese men.
32 citations