Multi-phenotype association decomposition: Unraveling complex gene-phenotype relationships

Deborah Weighill, Piet Jones, Carissa Bleker, Priya Ranjan, Manesh Shah, Nan Zhao, Madhavi Martin, Stephen DiFazio, David Macaya-Sanz, Jeremy Schmutz, Avinash Sreedasyam, Timothy Tschaplinski, Gerald Tuskan, Daniel Jacobson

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Various patterns of multi-phenotype associations (MPAs) exist in the results of Genome Wide Association Studies (GWAS) involving different topologies of single nucleotide polymorphism (SNP)-phenotype associations. These can provide interesting information about the different impacts of a gene on closely related phenotypes or disparate phenotypes (pleiotropy). In this work we present MPA Decomposition, a new network-based approach which decomposes the results of a multi-phenotype GWAS study into three bipartite networks, which, when used together, unravel the multi-phenotype signatures of genes on a genome-wide scale. The decomposition involves the construction of a phenotype powerset space, and subsequent mapping of genes into this new space. Clustering of genes in this powerset space groups genes based on their detailed MPA signatures. We show that this method allows us to find multiple different MPA and pleiotropic signatures within individual genes and to classify and cluster genes based on these SNP-phenotype association topologies. We demonstrate the use of this approach on a GWAS analysis of a large population of 882 Populus trichocarpa genotypes using untargeted metabolomics phenotypes. This method should prove invaluable in the interpretation of large GWAS datasets and aid in future synthetic biology efforts designed to optimize phenotypes of interest.

Original languageEnglish
Article number417
JournalFrontiers in Genetics
Volume10
Issue numberMAY
DOIs
StatePublished - 2019

Funding

Funding provided by The BioEnergy Science Center (BESC) and The Center for Bioenergy Innovation (CBI). U.S. Department of Energy Bioenergy Research Centers supported by the Office of Biological and Environmental Research in the DOE Office of Science. Support for the Poplar GWAS dataset was provided by The BioEnergy Science Center (BESC) and The Center for Bioenergy Innovation (CBI). U.S. Department of Energy Bioenergy Research Centers supported by the Office of Biological and Environmental Research in the DOE Office This research was also supported by the Plant-Microbe Interfaces Scientific Focus Area (http://pmi.ornl.gov) in the Genomic Science Program, the Office of Biological and Environmental Research (BER) in the U.S. Department of Energy Office of Science, and by the Department of Energy, Laboratory Directed Research and Development funding (7758), at the Oak Ridge National Laboratory. Oak Ridge National Laboratory is managed by UT-Battelle, LLC, for the US DOE under contract DE-AC05-00OR22725. An award of computer time was provided by the OLCF Directors Discretion program and the DOE INCITE program. This research used resources of the Oak Ridge Leadership Computing Facility (OLCF) and the Compute and Data Environment for Science (CADES) at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC05-00OR22725.

Keywords

  • GWAS
  • Hypothesis generation
  • Multi-phenotype associations
  • Networks
  • Pleiotropic signature
  • Pleiotropy
  • Powerset space
  • SNP clustering

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