Mystery Of Missing Genetic Disease Risk May Have Been Solved

redOrbit Staff & Wire Reports – Your Universe Online

If a combination of genetic variants are at least partially responsible for a person’s susceptibility to common diseases, then why has research to look for those genetic causes only successfully explained a fraction of the heritable risk of developing them? That’s the question that the authors of a new PLOS Genetics study set out to answer.

The study, which was led by scientists at the Institute of Cancer Research (ICR), London, demonstrates for the first time in cancer that some common genetic variants could actually indicate the presence of far more influential rare mutations that have not yet been discovered. Experts from over two dozen leading academic institutions participated in the research, which could help explain what the authors refer to as the mystery of the missing genetic risk.

“One important unanswered question in cancer genetics – and in genetics of common disease more generally – is why the genetic mutations we’ve discovered so far each seem to have such a small effect, when studies of families have shown that our genetic make-up has a very large influence on our risk of cancer,” said study co-leader and ICR oncogenetics professor Ros Eeles.

“Our study is an important step forward in our understanding of where we might find this ‘missing’ genetic risk in cancer,” Eeles, who is also an Honorary Clinical Consultant at The Royal Marsden NHS Foundation Trust, added in a statement. “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.”

Eeles and her colleagues recruited 20,440 men suffering from prostate cancer, as well as 21,469 without the disease, and identified a cluster of four common genetic variants on chromosome 17 which appeared to give rise to a slight increase in the risk of developing the condition (using standard statistical techniques). However, the study also revealed an alternative explanation for that risk signal in some of the study participants.

As it turns out, a small proportion of the men with the common chromosome 17 variants were also carriers of a rare mutation in a nearby gene (HOXB13) known to be associated with prostate cancer. With this so-called synthetic association, the number of men carrying a cancer risk variant was far lower than experts had initially believed, but those who did inherit a variant faced a higher-than-expected prostate cancer risk.

“The discovery shows that the prevailing genetic theory – that common cancers are predominantly caused by the combined action of many common genetic variants, each with only a very small effect – could potentially underestimate the impact of rare, as yet undiscovered mutations,” the Institute said. “The results are important because they show that there is a need for renewed effort by geneticists to find the causal variants, whether common or rare, behind the many common cancer-associated variants identified in recent years.”

“As far as we are aware, this is the first known example of a ‘synthetic association’ in cancer genetics,” study co-leader and ICR senior staff scientist Dr. Zsofia Kote-Jarai added. “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.”

Dr. Kote-Jarai went on to note that their research does not imply how widespread the phenomenon might be, but that it demonstrated how important it was to pinpoint the causal genetic changes behind the common variants already proven to influence disease susceptibility. The doctor also reported that large-scale sequencing studies might be needed to identify possible causal variants when fine-mapping genetic associations with disease.

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