New research suggests that common genetic variants implicated in disease susceptibility may be 'synthetic associations', detected only because of their correlation with a rarer variant that confers higher risk of the disease.
A long-standing problem in research into the genetics of common has been the puzzle of missing heritability – the inability to identify individual genetic variants that account for more than a fraction of the known overall heritable risk of that disease, based on studies of disease transmission in families.
In general, genetic susceptibility to common diseases is generally acknowledged to result from the presence of multiple common genetic variants, each conferring a very small increased risk of disease, though a few much rarer variants may confer a higher risk. However, even if these effects are combined the proportion of risk they confer together still falls short of the total genetic risk.
The HOXB13 gene on chromosome 17 has previously been implicated in prostate cancer susceptibility. Scientists from the Institute of Cancer Research (ICR) sequenced variants from over 20,000 prostate cancer patients and over 21,000 disease-free control subjects, in order to map this region more precisely.
Four common genetic variants were found to be associated with a modest increase in risk. However, further investigation revealed that these variants were linked to another, rarer variant (G84E) known to be associated with a substantially higher, moderate disease risk.
This finding is said to be ‘the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility’; and proposed as a potential explanation for the missing heritability of complex diseases.
Comment: This is a potentially important finding for genomic medicine, since if synthetic associations are identified in other common conditions, the results of many genome wide association studies (GWAS) may need to be revisited to see if they too have actually masked the presence of a smaller number of more clinically significant genetic variants with greater predictive power. Efforts to address this issue in breast cancer are already underway.
If missing heritability is revealed for more common diseases, this information could have a significant impact on screening programmes, as incorporating genetic data could allow more accurate disease risk prediction – and in turn, options to prevent disease or identify and treat it early, to improve health outcomes. The feasibility of such an approach has already been outlined (see previous news).