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Practical aspects of genome-wide association interaction analysis

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Large-scale epistasis studies can give new clues to system-level genetic mechanisms and a better understanding of the underlying biology of human complex disease traits. Though many novel methods have been proposed to carry out such studies, so far only a few of them have demonstrated replicable results. Here, we propose a minimal protocol for genome-wide association interaction (GWAI) analysis to identify gene–gene interactions from large-scale genomic data. The different steps of the developed protocol are discussed and motivated, and encompass interaction screening in a hypothesis-free and hypothesis-driven manner. In particular, we examine a wide range of aspects related to epistasis discovery in the context of complex traits in humans, hereby giving practical recommendations for data quality control, variant selection or prioritization strategies and analytic tools, replication and meta-analysis, biological validation of statistical findings and other related aspects. The minimal protocol provides guidelines and attention points for anyone involved in GWAI analysis and aims to enhance the biological relevance of GWAI findings. At the same time, the protocol improves a better assessment of strengths and weaknesses of published GWAI methodologies.

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The research was funded by the Belgian Science Policy Office Phase VII IAP network “Dynamical systems, control and optimization” (DYSCO II) and the Fonds de la Recherche Scientifique (FNRS). We thank our collaborators Jean-Charles Lambert and Céline Bellenguez (INSERM U744, Institut Pasteur de Lille, Universite de Lille Nord de France, Lille, France), Nilüfer Ertekin-Taner (Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA; Mayo Clinic Florida, Department of Neurology, Jacksonville, FL, USA), Denise Harold and Julie Williams (GERAD1 Consortium; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK) and our colleagues François Van Lishout, Jestinah M. Mahachie John and Kyrylo Bessonov from the Systems and Modeling Unit, Montefiore Institute, University of Liege, Belgium without whom the development of the GWAI protocol would not have been possible.

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The authors declare that they have no competing interests.

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Correspondence to Elena S. Gusareva.

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Gusareva, E.S., Van Steen, K. Practical aspects of genome-wide association interaction analysis. Hum Genet 133, 1343–1358 (2014).

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