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- Title
Local Joint Testing Improves Power and Identifies Hidden Heritability in Association Studies.
- Authors
Brown, Brielin C.; Price, Alkes L.; Patsopoulos, Nikolaos A.; Zaitlen, Noah
- 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.
- Subjects
HUMAN phenotype; MONOGENISM &; Polygenism (Human origins); SINGLE nucleotide polymorphisms; GENOTYPES; GENETICS
- Publication
Genetics, 2016, Vol 203, Issue 3, p1105
- ISSN
0016-6731
- Publication type
Article
- DOI
10.1534/genetics.116.188292