Genomewide Association Studies and Assessment of the Risk of Disease — NEJM

W. Gregory Feero, M.D., Ph.D., Editor, Alan E. Guttmacher, M.D., Editor

Genomewide Association Studies and Assessment of the Risk of Disease
Teri A. Manolio, M.D., Ph.D.

N Engl J Med 2010; 363:166-176July 8, 2010

Source Information
From the Office of Population Genomics, National Human Genome Research Institute, Bethesda, MD.

Address reprint requests to Dr. Manolio at the Office of Population Genomics, National Human Genome Research Institute, Bldg. 31, Rm. 4B-09, 31 Center Dr., MSC 2152, Bethesda, MD 20892, or at manolio@nih.gov.

The Genomewide Association Study.) — have revolutionized the search for genetic influences on complex traits.1,2 Such conditions, in contrast with single-gene disorders, are caused by many genetic and environmental factors working together, each having a relatively small effect and few if any being absolutely required for disease to occur. Although complex conditions have been referred to as the geneticist's nightmare,3 in the past 5 years genomewide association studies have identified SNPs implicating hundreds of robustly replicated loci (i.e., specific genomic locations) for common traits.4

These studies raise many questions, such as why the identified variants have low associated risks and account for so little heritability.5 Explanations for this apparent gap are being sought. Perhaps the answer will reside in rare variants (see the Glossary for this and other key terms), which are not captured by current genomewide association studies; structural variants, which are poorly captured by current studies; other forms of genomic variation; or interactions between genes or between genes and environmental factors.6 Despite their value in locating the vicinity of genomic variants that may be causing disease, few of the SNPs identified in genomewide association studies have clear functional implications that are relevant to mechanisms of disease.7 Narrowing an implicated locus to a single variant that directly causes susceptibility to disease by disrupting the expression or function of a protein has proved elusive to date. This will be a key step in improving our understanding of the mechanisms of disease and in designing effective strategies for risk assessment and treatment.

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Genomewide Association Studies and Assessment of the Risk of Disease — NEJM