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Unformatted text preview: T h e new england journal o f medicine n engl j med 360;17 nejm.org april 23, 2009 1759 review article Current Concepts Genomewide Association Studies and Human Disease John Hardy, Ph.D., and Andrew Singleton, Ph.D. From the Institute of Neurology, Univer- sity College London, London (J.H.); and the Laboratory of Neurogenetics, Bethes- da, MD (A.S.). Address reprint requests to Dr. Hardy at the Institute of Neurology, University College London, Queen Sq., London WC1N 3BG, United Kingdom, or at email@example.com. This article (10.1056/NEJMra0808700) was published at NEJM.org on April 15, 2009. N Engl J Med 2009;360:1759-68. Copyright 2009 Massachusetts Medical Society. F or 20 years, genetic linkage c ombined with positional cloning has offered a rational and increasingly straightforward route to finding gene mutations that lead to monogenic disease, such as cystic fibrosis and Hunting- tons disease (see the Glossary). With a few important exceptions, these searches have led to mutations that alter the amino acid sequence of a protein and that enor- mously increase the risk of disease. During the past few years, genomewide association studies have identified a large number of robust associations between specific chromosomal loci and com- plex human disease, such as type 2 diabetes and rheumatoid arthritis 1 (Fig. 1). This approach relies on the foundation of data produced by the International Human HapMap Project and the fact that genetic variance at one locus can predict with high probability genetic variance at an adjacent locus, typically over distances of 30,000 base pairs of DNA 2 in the human genome, which contains about 310 9 base pairs. This haplotypic structure of the human genome means that it is possible to survey the genome for common variability associated with the risk of disease simply by genotyping approximately 500,000 judiciously chosen markers in the genome of several thousand case subjects and control subjects. 3 Consequently, it is now routine to identify common, low-risk variants (i.e., those that are present in more than 5% of the population) that confer a small risk of disease, typically with odds ratios of 1.2 to 5.0. 4 The platform that is used to genotype markers in genomewide association stud- ies and related approaches has uncovered a startling degree of structural genomic variation. Although such variants were known to be causes of rare monogenic dis- orders, 5,6 the extent of structural genomic variation among persons was largely unanticipated, and there is increasing interest in understanding how such variants may confer a risk of common diseases. 7,8 The initial contention surrounding the viability of genomewide association stud- ies has largely subsided. However, discussion has centered on evaluating how far such studies will take us in understanding the risks and causes of disease and thus the time and resources that should be invested in genotyping more case sub- jects with any one disease to garner what many see as diminishing genetic returns. jects with any one disease to garner what many see as diminishing genetic returns....
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