title: Local Joint Testing Improves Power and Identifies Hidden Heritability in Association Studies.
abstract: 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 led 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 (WTCCC) data set leads to the discovery of 22 associated loci, 5 more than the marginal approach. These loci were later found in follow-up studies containing thousands of additional individuals. We find that these loci significantly increase the heritability explained by genome-wide significant associations in the WTCCC data set. Furthermore, we show that local joint testing in a cis-expression QTL (eQTL) study of the gEUVADIS data set increases the number of genes containing significant eQTL 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.
authors.affiliation: Department of Computer Science, University of California, Berkeley, California 94720 brielin@berkeley.edu.
authors.forename: Brielin C
authors.initials: BC
authors.lastname: Brown
authors.affiliation: Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts 02115.
authors.forename: Alkes L
authors.initials: AL
authors.lastname: Price
authors.affiliation: Department of Neurology, Brigham & Women's Hospital, Boston, Massachusetts 02115 Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02115 Broad Institute, Cambridge, Massachusetts 02142.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.affiliation: Department of Medicine, University of California, San Francisco, California 94158.
authors.forename: Noah
authors.initials: N
authors.lastname: Zaitlen
mesh_terms: D004843:Epistasis, Genetic; D015870:Gene Expression / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D012984:Software
keywords: epistasis; heritability; joint testing; polygenicity; statistical genetics