Journal Article

Finding the missing heritability of complex diseases

Boehnke, Michael, Clark, Andrew G., Hindorff, Lucia A., Rotimi, Charles N., Collins, Francis S., Cho, Judy H., Whittemore, Alice S., Kong, Augustine, Goldstein, David B., Gibson, Greg, Guttmacher, Alan E., Slatkin, Montgomery, Visscher, Peter M., Cardon, Lon R., Mardis, Elaine, Eichler, Evan E., Ramos, Erin M., Manolio, Teri A., McCarthy, Mark I., Haines, Jonathan L., McCarroll, Steven A., Hunter, David J., Cox, Nancy J., Valle, David, Kruglyak, Leonid, Chakravarti, Aravinda, Mackay, Trudy F. C.

2009

Overview

Genetics of complex diseases Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases, but most confer quite small increments of risk. There seems to be a large component of heritability somehow evading detection. Possible explanations for this 'missing heritability' include great numbers of small-effect variants yet to be found, rare structural or epigenetic variation not detected by current genotyping technology and hard-to-detect gene–gene and gene–environment interactions. Teri Manolio and colleagues examine the research strategies most likely to distinguish between these and other possible explanations. Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, ‘missing’ heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Autism / Biological and medical sciences / Crohn's disease / Disease prevention / Diseases / General aspects / Genetic aspects / Genetic Diseases, Inborn - genetics / Genetic Predisposition to Disease - genetics / Genetic variance / Genetics / Genetics, Medical - methods / Genetics, Medical - trends / Genome-Wide Association Study - methods / Genome-Wide Association Study - trends / Genomes / Health aspects / Heritability / Humanities and Social Sciences / Humans / Inheritance Patterns - genetics / Medical sciences / multidisciplinary / Pedigree / review-article / Science / Science (multidisciplinary) / United States