Genomic Prediction of disease risk using polygenic scores (Nature Genetics)

Written by: Stephen Hsu

Primary Source: Information Processing, 8/14/18.

It seems to me we are just at the tipping point — soon it will be widely understood that with large enough data sets we can predict complex traits and complex disease risk from genotype, capturing most of the estimated heritable variance. People will forget that many “experts” doubted this was possible — the term missing heritability will gradually disappear.

In just a few years genotyping will start to become “standard of care” in many health systems. In 5 years there will be ~100M genotypes in storage (vs ~20M now), a large fraction available for scientific analysis.

Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations (Nature Genetics)

A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2,3,4,5, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk6. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.

See also Genomic Prediction: A Hypothetical (Embryo Selection) and Accurate Genomic Prediction Of Human Height.

From the paper:

Using much larger studies and improved algorithms, we set out to revisit the question of whether a GPS can identify subgroups of the population with risk approaching or exceeding that of a mono- genic mutation. We studied five common diseases with major public health impact: CAD, atrial fibrillation, type 2 diabetes, inflamma- tory bowel disease, and breast cancer.

For each of the diseases, we created several candidate GPSs based on summary statistics and imputation from recent large GWASs in participants of primarily European ancestry (Table 1). Specifically, we derived 24 predictors based on a pruning and thresholding method, and 7 additional predictors using the recently described LDPred algorithm13 (Methods, Fig. 1 and Supplementary Tables 1–6). These scores were validated and tested within the UK Biobank, which has aggregated genotype data and extensive phenotypic information on 409,258 participants of British ancestry (average age: 57 years; 55% female)14,15.

We used an initial validation dataset of the 120,280 participants in the UK Biobank phase 1 genotype data release to select the GPSs with the best performance, defined as the maximum area under the receiver-operator curve (AUC). We then assessed the performance in an independent testing dataset comprised of the 288,978 partici- pants in the UK Biobank phase 2 genotype data release. For each disease, the discriminative capacity within the testing dataset was nearly identical to that observed in the validation dataset.

In the talk below @21:45 I discuss prospects for genomic prediction of disease risk.

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Stephen Hsu
Stephen Hsu is vice president for Research and Graduate Studies at Michigan State University. He also serves as scientific adviser to BGI (formerly Beijing Genomics Institute) and as a member of its Cognitive Genomics Lab. Hsu’s primary work has been in applications of quantum field theory, particularly to problems in quantum chromodynamics, dark energy, black holes, entropy bounds, and particle physics beyond the standard model. He has also made contributions to genomics and bioinformatics, the theory of modern finance, and in encryption and information security. Founder of two Silicon Valley companies—SafeWeb, a pioneer in SSL VPN (Secure Sockets Layer Virtual Private Networks) appliances, which was acquired by Symantec in 2003, and Robot Genius Inc., which developed anti-malware technologies—Hsu has given invited research seminars and colloquia at leading research universities and laboratories around the world.