NEJM-Hirschhorn09_pathways

NEJM-Hirschhorn09_pathways - PE R S PE C T IV E Genomewide...

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n engl j med 360;17 nejm.org april 23 , 2009 PERSPECTIVE 1699 Genomewide Association Studies — Illuminating Biologic Pathways Joel N. Hirschhorn, M.D., Ph.D. Genomewide Association Studies — Illuminating Biologic Pathways H uman geneticists seek to understand the inherited ba- sis of human biology and disease, aiming either to gain insights that could eventually improve treatment or to produce useful diagnostic or predictive tests. As recently as 2004, few genetic variants were known to reproducibly influence common polygenic diseases (in- cluding cancer, coronary artery disease, and diabetes) or quanti- tative phenotypes (including lipid levels and blood pressure). This relative ignorance limited poten- tial insights into the pathophysi- ology of common diseases. The completion of the human genome sequence in 2005 and the provision of an initial catalogue of human genetic variation and a haplotype map (known as the HapMap), together with rapid im- provements in genotyping tech- nology and analysis, have per- mitted genomewide association s tud ies to be unde r taken in a large number of samples. 1 In the first and current implementation of this approach, the great major- ity of genetic variants with pop- ulation frequencies of 5% or more could be tested directly or indirectly for association with disease risk or quantitative traits — thus providing a potential path to gene discovery for polygenic diseases and traits. Before the initiation of ge- nomewide association studies, there was considerable and healthy skepticism about their likely suc- cess. For example, in 2005, two friends and well-known geneti- cists, Francis Collins and Thomas Gelehrter, made a public bet: Gelehrter predicted that no more than three new common variants would be reproducibly associated with common diseases by the time the American Society of Hu- man Genetics (ASHG) held its meeting in the autumn of 2008. During the past 2 years, how- ever, genomewide association studies have identified more than 250 genetic loci in which com- mon genetic variants occur that are reproducibly associated with polygenic traits. 1-4 This explosion represents one of the most pro- lific periods of discovery in hu- man genetics, with most new loci identified in genomewide asso- ciation studies published during the past 18 months. The bet was settled: Collins was the clear win- ner, by a margin of more than 200 new associated variants. New skeptics have now ques- tioned the value of these recent discoveries. They cite the modest effect sizes of common variants, both individually and in combi- nation, and argue that the small fraction of heritability that is ex- plained by these variants pre- cludes practical prediction or meaningful biologic insights. A
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NEJM-Hirschhorn09_pathways - PE R S PE C T IV E Genomewide...

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