Plenge Lab
Date posted: March 13, 2013 | Author: | No Comments »

Categories: Human Genetics Precision Medicine

The value of genetics to clinical prediction depends upon the underlying genetic architecture of complex traits (including disease risk and drug efficacy/toxicity).  It is increasingly clear that common variants contribute to common phenotypes, but that extremely large sample sizes are required to tease apart true signal from the noise at a stringent level of statistical significance.  Occasionally, common variants have a large effect on common phenotypes (e.g., MHC alleles and risk of autoimmunity; VKORC1 and warfarin metabolism), but this seems to be the exception rather than the rule.

 A recent paper published in Nature Genetics explores this concept in more detail (download PDF here).  As stated in the manuscript by Chatterjee and colleagues: “The gap between estimates of heritability based on known loci and those estimated owing to the comprehensive set of common susceptibility variants raises the possibility of substantially improving prediction performance of risk models by using a polygenic approach, one that includes many SNPs that do not reach the stringent threshold for genome-wide significance.”  They measure the ability of models based on current as well as future GWAS to improve the prediction of individual traits.  

The results, which are intriguing, depend not only on the underlying genetic architecture (which is often unknown, especially for PGx traits), but also disease prevalence and familial aggregation:  “We observed that for less common, highly familial conditions, such as T1D and Crohn’s disease, risk models that include family history and optimal polygenic scores based on current GWAS can identify a large majority of cases by targeting a small group of high-risk individuals (for example, subjects who fall in the highest quintile of risk).

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