Cancer researchers have found part of the answer in the case of the 'missing heritability' — the mismatch between genetic disease risk and common genetic variants.
It has long been thought that common variants might be weakly linked to disease because they are co-inherited with rare, nearby genetic variants. These variants are much more predictive of disease, but are themselves too rare to be discovered, even in studies with large sample sizes.
Zsofia Kote-Jarai of the Institute for Cancer Research in Sutton, UK, and her colleagues report the first evidence for this 'synthetic association' in cancer. They show that four common genetic variants in or near the HOXB13 gene are associated with a roughly 30% increase in cancer risk and are almost always inherited with a rare gene variant, which itself predicts an approximately 400% increase in risk for the disease.
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Unmasking the real risk genes. Nature 506, 269 (2014). https://doi.org/10.1038/506269b
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DOI: https://doi.org/10.1038/506269b
