For many within the scientific and medical communities, as well as within the media and wider public, the sequencing of the human genome seemed to hold the promise of rapidly revealing the genetic basis of most common human diseases, as well as offer direction in the development of effective treatments. However, over a decade later, this outcome is widely considered to have failed. Much of this perceived failure is related to disappointment over the seemingly underwhelming results of the many genome-wide association studies (GWAS) published in the last six years. Initially anticipated to be a powerful way to link key human genetic variants with phenotypes, GWAS have tended instead to identify many alleles with very small affect on phenotype, leading to what has been dubbed the "missing heritability" problem. Possible explanations for missing heritability include a larger role of the environment in common diseases, the importance of alleles with large effects that occur in < 5% of the population, or the contribution of huge numbers of alleles of effect sizes to small to be detected by GWAS. This paper discusses how disappointment in GWAS is forcing a change in our understanding of the architecture of human disease and genetic heritability in humans more broadly.
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