title: Genome-wide association data reveal a global map of genetic interactions among protein complexes.
abstract: This work demonstrates how gene association studies can be analyzed to map a global landscape of genetic interactions among protein complexes and pathways. Despite the immense potential of gene association studies, they have been challenging to analyze because most traits are complex, involving the combined effect of mutations at many different genes. Due to lack of statistical power, only the strongest single markers are typically identified. Here, we present an integrative approach that greatly increases power through marker clustering and projection of marker interactions within and across protein complexes. Applied to a recent gene association study in yeast, this approach identifies 2,023 genetic interactions which map to 208 functional interactions among protein complexes. We show that such interactions are analogous to interactions derived through reverse genetic screens and that they provide coverage in areas not yet tested by reverse genetic analysis. This work has the potential to transform gene association studies, by elevating the analysis from the level of individual markers to global maps of genetic interactions. As proof of principle, we use synthetic genetic screens to confirm numerous novel genetic interactions for the INO80 chromatin remodeling complex.
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Hannum
authors.forename: Rohith
authors.initials: R
authors.lastname: Srivas
authors.forename: Aude
authors.initials: A
authors.lastname: Guénolé
authors.forename: Haico
authors.initials: H
authors.lastname: van Attikum
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.forename: Richard M
authors.initials: RM
authors.lastname: Karp
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
mesh_terms: D016000:Cluster Analysis; D053263:Gene Regulatory Networks; D005819:Genetic Markers; D016681:Genome, Fungal / Q000235:genetics*; D055106:Genome-Wide Association Study; D046912:Multiprotein Complexes / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D005819:Genetic Markers; C483404:INO80 complex, S cerevisiae; D046912:Multiprotein Complexes; D029701:Saccharomyces cerevisiae Proteins