Unified Sequence-Based Association Tests Allowing for Multiple Functional Annotations and Meta-analysis of Noncoding Variation in Metabochip Data  Zihuai He, Bin Xu, Seunggeun Lee, Iuliana Ionita-Laza  The American Journal of Human Genetics  Volume 101, Issue 3, Pages 340-352 (September 2017) DOI: 10.1016/j.ajhg.2017.07.011 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Type I Error Rate of Integrating Multiple Functional Scores Empirical type I error rate was estimated as the proportion of p values less than α = 0.001 on the basis of 104 replicates. The different curves correspond to quantitative trait and dichotomous trait. The dashed line corresponds to the α level. The American Journal of Human Genetics 2017 101, 340-352DOI: (10.1016/j.ajhg.2017.07.011) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Power Comparison with Existing Methods Each bar presents the empirical power estimated as the proportion of p values less than α = 2.5 × 10−6 on the basis of 104 replicates. Abbreviations are as follows: P1 and P2, the probability that the functional score 1 and 2, respectively, can predict the risk effect; O, original dispersion (SKAT), burden, or combined (SKAT-O) test with beta(1,25) as weights; W1, weighted dispersion (SKAT), burden, or combined (SKAT-O) test with beta(1,25) × functional score as new weights; U1 and U1+2, proposed unified dispersion, burden, or combined test incorporating one and two functional scores, respectively. The American Journal of Human Genetics 2017 101, 340-352DOI: (10.1016/j.ajhg.2017.07.011) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Power of Integrating Multiple Functional Scores βj=0.8|log10mj|, where mj is the MAF for the jth variant. The causal proportion is 10%. Each curve presents the empirical power estimated as the proportion of p values less than α = 0.001 on the basis of 104 replicates. The solid curves correspond to the power of the proposed unified tests incorporating 0 (the original tests) to 20 all predictive, all non-predictive, or a mixture of predictive (first three) functional scores. The black line corresponds to the ideal setting of applying the original tests (dispersion, burden, and combined) by using the causal variants only. The dashed curves correspond to the average correlations between the true effect sizes and the weight that results in the minimum p value. The American Journal of Human Genetics 2017 101, 340-352DOI: (10.1016/j.ajhg.2017.07.011) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 4 Power of Integrating Multiple Functional Scores βj=0.2|log10mj| for quantitative traits and βj=0.4|log10mj| for dichotomous traits, where mj is the MAF for the jth variant. The causal proportion is 50%. Each curve presents the empirical power estimated as the proportion of p values less than α = 0.001 on the basis of 104 replicates. The solid curves correspond to the power of the proposed unified tests incorporating 0 (the original tests) to 20 all predictive, all non-predictive, or a mixture of predictive (first three) functional scores. The black line corresponds to the ideal setting of applying the original tests (dispersion, burden, and combined) by using the causal variants only. The dashed curves correspond to the average correlations between the true effect sizes and the weight that results in the minimum p value. The American Journal of Human Genetics 2017 101, 340-352DOI: (10.1016/j.ajhg.2017.07.011) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 5 Individual Variant p Value and Eigen-Phred Score for the Rare (MAF < 0.05) Noncoding Variants in the Metabochip Region Indexed by rs2048327 The American Journal of Human Genetics 2017 101, 340-352DOI: (10.1016/j.ajhg.2017.07.011) Copyright © 2017 American Society of Human Genetics Terms and Conditions