Genomic Prediction of 16 Complex Disease Risks Including Heart Attack, Diabetes, Breast and Prostate Cancer (Nature Scientific Reports)

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Genomic Prediction of 16 Complex Disease Risks Including Heart Attack, Diabetes, Breast and Prostate Cancer

Louis Lello, Timothy G. Raben, Soke Yuen Yong, Laurent C. A. M. Tellier & Stephen D. H. Hsu

Nature Scientific Reports volume 9, Article number: 15286 (2019)

We construct risk predictors using polygenic scores (PGS) computed from common Single Nucleotide Polymorphisms (SNPs) for a number of complex disease conditions, using L1-penalized regression (also known as LASSO) on case-control data from UK Biobank. Among the disease conditions studied are Hypothyroidism, (Resistant) Hypertension, Type 1 and 2 Diabetes, Breast Cancer, Prostate Cancer, Testicular Cancer, Gallstones, Glaucoma, Gout, Atrial Fibrillation, High Cholesterol, Asthma, Basal Cell Carcinoma, Malignant Melanoma, and Heart Attack. We obtain values for the area under the receiver operating characteristic curves (AUC) in the range ~0.58–0.71 using SNP data alone. Substantially higher predictor AUCs are obtained when incorporating additional variables such as age and sex. Some SNP predictors alone are sufficient to identify outliers (e.g., in the 99th percentile of polygenic score, or PGS) with 3–8 times higher risk than typical individuals. We validate predictors out-of-sample using the eMERGE dataset, and also with different ancestry subgroups within the UK Biobank population. Our results indicate that substantial improvements in predictive power are attainable using training sets with larger case populations. We anticipate rapid improvement in genomic prediction as more case-control data become available for analysis.

From the Discussion:

The significant heritability of most common disease conditions implies that at least some of the variance in risk is due to genetic effects. With enough training data, modern machine learning techniques enable us to construct polygenic predictors of risk. A learning algorithm with enough examples to train on can eventually identify individuals, based on genotype alone, who are at unusually high risk for the condition. This has obvious clinical applications: scarce resources for prevention and diagnosis can be more efficiently allocated if high risk individuals can be identified while still negative for the disease condition. This identification can occur early in life, or even before birth.

In this paper we used UK Biobank data to construct predictors for a number of conditions. We conducted out of sample testing using eMERGE data (collected from the US population) and adjacent ancestry (AA) testing using UK ethnic subgroups distinct from the training population. The results suggest that our polygenic scores indeed predict complex disease risk - there is very strong agreement in performance between the training and out of sample testing populations. Furthermore, in both the training and test populations the distribution of PGS is approximately Gaussian, with cases having on average higher scores. We verify that, for all disease conditions studied, a simple model of displaced Gaussian distributions predicts empirically observed odds ratios (i.e., individual risk in test population) as a function of PGS. This is strong evidence that the polygenic score itself, generated for each disease condition using machine learning, is indeed capturing a nontrivial component of genetic risk.

By varying the amount of case data used in training, we estimate the rate of improvement of polygenic predictors with sample size. Plausible extrapolations suggest that sample sizes readily within reach of population genetics studies will result in predictors of significant clinical utility. ...