全基因组关联研究（GWAS）发现了数百种与复杂人类疾病相关的基因突变，但这些突变大部分对增加患病风险的贡献都非常小。遗传性似乎有一大部分无法被检测到。人们对遗传性中未能检测到的这一部分提出以下可能的解释：影响较小的大量变异体尚未发现；存在一些当前的基因型分析技术无法检测到的罕见的结构变异或表观遗传变异；以及存在难以检测到的基因与基因之间和基因与环境之间的相互作用。
在一篇“Review”文章中，Teri Manolio及其同事对最有可能将这些解释和其他可能的解释加以区分的研究策略进行了分析。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 461, 747-753 (8 October 2009) | doi:10.1038/nature08494
Finding the missing heritability of complex diseases
Teri A. Manolio1, Francis S. Collins2, Nancy J. Cox3, David B. Goldstein4, Lucia A. Hindorff5, David J. Hunter6, Mark I. McCarthy7, Erin M. Ramos5, Lon R. Cardon8, Aravinda Chakravarti9, Judy H. Cho10, Alan E. Guttmacher1, Augustine Kong11, Leonid Kruglyak12, Elaine Mardis13, Charles N. Rotimi14, Montgomery Slatkin15, David Valle9, Alice S. Whittemore16, Michael Boehnke17, Andrew G. Clark18, Evan E. Eichler19, Greg Gibson20, Jonathan L. Haines21, Trudy F. C. Mackay22, Steven A. McCarroll23 & Peter M. Visscher24
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.
