bioRxiv preprint doi: https://doi.org/10.1101/2020.09.24.312421; this version posted September 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 1 Pathway Analysis within Multiple Human Ancestries Reveals 2 Novel Signals for Epistasis in Complex Traits 3 1,2,y 2,3 2,4,*,y 1,2,*,y 4 Michael C. Turchin , Gregory Darnell , Lorin Crawford , and Sohini Ramachandran 5 1 Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, 6 USA 7 2 Center for Computational Molecular Biology, Brown University, Providence, RI, USA 8 3 Institute for Computational and Experimental Research in Mathematics (ICERM), 9 Brown University, Providence, RI, USA 10 4 Microsoft Research New England, Cambridge, MA, USA 11 *: Authors Contributed Equally 12 y Corresponding E-mail:
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[email protected] 14 Abstract 15 Genome-wide association (GWA) studies have identified thousands of significant genetic associations in 16 humans across a number of complex traits. However, the majority of these studies focus on linear additive 17 relationships between genotypic and phenotypic variation. Epistasis, or non-additive genetic interactions, 18 has been identified as a major driver of both complex trait architecture and evolution in multiple model 19 organisms; yet, this same phenomenon is not considered to be a significant factor underlying human 20 complex traits. There are two possible reasons for this assumption.