There is mounting evidence that complex human phenotypes are highly polygenic, with many loci harboring multiple causal variants, yet most genetic association studies examine each SNP in isolation. While this has lead to the discovery of thousands of disease associations, discovered variants account for only a small fraction of disease heritability. Alternative multi-SNP methods have been proposed, but issues such as multiple testing correction, sensitivity to genotyping error, and optimization for the underlying genetic architectures remain. Here we describe a local joint testing procedure, complete with multiple testing correction, that leverages a genetic phenomenon we call linkage masking wherein linkage disequilibrium between SNPs hides their signal under standard association methods. We show that local joint testing on the original Wellcome Trust Case Control Consortium dataset leads to the discovery of 29% more associated loci that were later found in followup studies containing thousands of additional individuals. These loci double the heritability explained by genome-wide significant associations in the WTCCC dataset, implicating linkage masking as a novel source of missing heritability. Furthermore, we show that local joint testing in a cis-eQTL study of the gEUVADIS dataset increases the number of genes discovered by 10.7% over marginal analyses. Our multiple hypothesis correction and joint testing framework are available in a python software package called jester, available at github.com/brielin/ Jester.
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