New discovery could uncover ‘missing link’ in genetics

Researchers believe that susceptibility to common diseases stems from a combination of common genetic variants and a variety of rare genetic mutations. But this only accounts for a small proportion of potential heritable risk factors for disease. Now, new research has discovered that some genetic variants could indicate the presence of rare genetic mutations that have yet to be discovered, which may contribute to the risk of common diseases.

This is according to a study recently published in the journal PLOS Genetics.

Investigators from the Institute of Cancer Research (ICR) in the UK analyzed 20,440 men with prostate cancer alongside 21,469 men without the disease.

From this, the researchers discovered a cluster of four common genetic variants present on chromosome 17. These variants seemed to contribute to a small increase in the risk of prostate cancer.

Further investigation revealed that some of the men who possessed these genetic variants had a rare mutation in HOXB13 – a gene associated with prostate cancer.

They refer to the link between the genetic variants and the rare mutation as a “synthetic association.”

The researchers note that under this synthetic association, there was a much lower number of people carrying a cancer risk variant than what had been assumed.

However, individuals who did inherit a cancer risk variant actually had a much higher prostate cancer risk than was previously known.

Common genetic theory ‘may underestimate cancer risk of rare mutations’

Common genetic theory is that cancers are mainly caused by a combination of genetic variants that each only have a small impact. But the researchers say their findings suggest that this theory may underestimate the impact of rare mutations that have yet to be discovered.

Dr. Zsofia Kote-Jarai, of the ICR and co-leader of the study, says this research demonstrates the first known example of a synthetic association in cancer genetics.

She adds:

“It was exciting to find evidence for this theory, which predicts that common genetic variants that appear to increase risk of disease by only a modest amount may indeed sometimes be detected purely due to their correlation with a rarer variant which confers a greater risk.”

Furthermore, Dr. Kote-Jarai says although the study does not indicate how widespread this synthetic association is, it may hold important information for geneticists when analyzing cancer and other common diseases.

She notes the findings emphasize the importance of establishing causal genetic changes in common variants that have already been found to impact the risk of disease.

“Our study also demonstrates that standard methods to identify potential causal variants when fine-mapping genetic associations with disease may be inadequate to assess the contribution of rare variants. Large sequencing studies may be necessary to answer these questions unequivocally,” she adds.

Prof. Ros Eeles, of the ICR and The Royal Marsden NHS Foundation Trust in the UK and co-leader of the study, notes that there has been an important unanswered question in the genetics of cancer and other common diseases:

Why do the genetic mutations that have already been discovered have such a small impact when research has shown that genetic make-up largely influences the risk of cancer?

Prof. Eeles says:

“Our study is an important step forward in our understanding of where we might find this ‘missing’ genetic risk in cancer. At least in part, it might lie in rarer mutations which current research tools have struggled to find, because individually each does not affect a large number of people.”

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