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Nat Commun. 2019 Sep 19;10(1):4274. doi: 10.1038/s41467-019-12131-7.

Discovering genetic interactions bridging pathways in genome-wide association studies.

Author information

1
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. gang.fang@mssm.edu.
2
Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN, 55455, USA.
3
Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.
4
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, 55455, USA.
5
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
6
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
7
Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN, 55455, USA. kumar@cs.umn.edu.
8
Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN, 55455, USA. chadm@umn.edu.

Abstract

Genetic interactions have been reported to underlie phenotypes in a variety of systems, but the extent to which they contribute to complex disease in humans remains unclear. In principle, genome-wide association studies (GWAS) provide a platform for detecting genetic interactions, but existing methods for identifying them from GWAS data tend to focus on testing individual locus pairs, which undermines statistical power. Importantly, a global genetic network mapped for a model eukaryotic organism revealed that genetic interactions often connect genes between compensatory functional modules in a highly coherent manner. Taking advantage of this expected structure, we developed a computational approach called BridGE that identifies pathways connected by genetic interactions from GWAS data. Applying BridGE broadly, we discover significant interactions in Parkinson's disease, schizophrenia, hypertension, prostate cancer, breast cancer, and type 2 diabetes. Our novel approach provides a general framework for mapping complex genetic networks underlying human disease from genome-wide genotype data.

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