Last week we
posted a new paper (see bottom), prepared for the book
Genomic Prediction of Complex Traits, Springer Nature series
Methods in Molecular Biology.
Someone asked me to comment more on clinical applications of polygenic risk scores. Here's what we say in the paper, using the specific example of breast cancer (emphasis added):
There is already signifcant interest in the application of PRS in a clinical setting, for example to identify high risk individuals who might receive early screening or preventative care [2, 13–24]. As a concrete example, women with high PRS scores for breast cancer can be offered early screening: already standard of care for those with BRCA risk variants [25, 26]. However, BRCA mutations affect no more than a few women per thousand in the general population [27–29]. Importantly, the number of (BRCA negative) women who are at high risk for breast cancer due to polygenic effects is an order of magnitude larger than the population of BRCA carriers [2, 10, 30–34]. From this one example it is clear that significant medical, public health, and cost benefits could result from PRS (e.g. [35]). It is well known that patients with atherosclerotic diseases, coronary artery disease (CAD), and lung diseases can benefit from early intervention [36–38]. ... Precision genetics is already used in identification of candidates for early intervention, and will become widespread in the near future (cf. Myriad’s riskScore test and other examples [33, 34]). In figure 4, we illustrate the predicted risk of breast cancer and coronary artery disease as function of age for high, medium and low risk groups, respectively.
We have verified in sibling studies that among two sisters the outlier with high risk score is much more likely to have breast cancer than the one with normal range score. The excerpt below is from the section on sibling validation:
... We tested a variety of polygenic predictors using tens of thousands of genetic siblings for whom we have SNP genotypes, health status, and phenotype information in late adulthood. Siblings have typically experienced similar environments during childhood, and exhibit negligible population stratification relative to each other. Therefore, the ability to predict differences in disease risk or complex trait values between siblings is a strong test of genomic prediction in humans. We compare validation results obtained using non-sibling subjects to those obtained among siblings and find that typically most of the predictive power persists in within-family
designs. Given 1 sibling with normal-range PRS score (less than 84th percentile) and 1 sibling with high PRS score (top few percentiles), the predictors identify the affected sibling about 70-90 percent of the time across a variety of disease conditions, including breast cancer, heart attack, diabetes, etc. For height, the predictor correctly identities the taller sibling roughly 80 percent of the time when the (male) height difference is 2 inches or more.
The evidence is strong that PRS outliers are at unusual absolute risk. In fact, the likelihood that an individual in the high PRS tail will eventually have the disease can approach 100% for some conditions -- see figure below. This is a concrete realization of precision medicine, at least for these individuals.
In addition to commercial products like Myriad's riskScore (which extends their BRCA panel to additional polygenic factors, and is already widely available), I am aware of many healthcare systems (including some national healthcare systems) that are seriously investigating the use of PRS in standard clinical care.
Another example: a relative of mine had a prostate cancer diagnosis and took a (standard of care) genetic risk test which, like the pre-riskScore Myriad product, is simply a panel of rare monogenic risk variants. We and other groups have developed prostate cancer polygenic predictors which could be easily incorporated into standard of care and would likely be much more useful than the existing panel. I haven't looked carefully at the prostate cancer numbers but I strongly suspect that, as in the breast cancer example, many more men are at high risk due to high PRS than are carriers of the rare variants.
It's only a matter of time before these improvements in diagnostic screening become widespread.
Here is what we say about IVF applications:
In the past, parents with more viable embryos than they intended to use made a selection based on very little information — typically nothing more than the appearance or morphology of each blastocyst. With modern technology it has become common to genotype embryos before selection, in order to detect potential genetic issues such as trisomy 21 (Down Syndrome). Parents who are carriers of a single gene variant linked to a Mendelian condition can use genetic screening to avoid passing the risk variant on to their child. Millions of embryos are now genetically tested each year. With polygenic risk prediction, it is possible now to screen against outlier risk for many common disease conditions, not just rare single gene conditions. For example, the overwhelming majority of families with breast cancer history are not carriers of a BRCA risk variant, but rather have elevated polygenic risk. It is now possible for these families to select an embryo with average or even below average breast cancer risk if they so wish.
Here is the paper:
From Genotype to Phenotype: polygenic prediction of complex human traits
arXiv.org > q-bio > arXiv:2101.05870 33 pages, 7 figures, 1 table
Timothy G. Raben, Louis Lello, Erik Widen, Stephen D.H. Hsu
Decoding the genome confers the capability to predict characteristics of the organism (phenotype) from DNA (genotype). We describe the present status and future prospects of genomic prediction of complex traits in humans. Some highly heritable complex phenotypes such as height and other quantitative traits can already be predicted with reasonable accuracy from DNA alone. For many diseases, including important common conditions such as coronary artery disease, breast cancer, type I and II diabetes, individuals with outlier polygenic scores (e.g., top few percent) have been shown to have 5 or even 10 times higher risk than average. Several psychiatric conditions such as schizophrenia and autism also fall into this category. We discuss related topics such as the genetic architecture of complex traits, sibling validation of polygenic scores, and applications to adult health, in vitro fertilization (embryo selection), and genetic engineering.
