A Robust Method Uncovers Significant Context-Specific Heritability in Diverse Complex Traits.

TitleA Robust Method Uncovers Significant Context-Specific Heritability in Diverse Complex Traits.
Publication TypeJournal Article
Year of Publication2020
AuthorsDahl, A, Nguyen, K, Cai, N, Gandal, MJ, Flint, J, Zaitlen, N
JournalAm J Hum Genet
Date Published2020 01 02
KeywordsAdult, Animals, Computer Simulation, Female, Gene-Environment Interaction, Genetic Markers, Genome-Wide Association Study, Humans, Male, Mental Disorders, Middle Aged, Models, Genetic, Multifactorial Inheritance, Phenomics, Phenotype, Rats

Gene-environment interactions (GxE) can be fundamental in applications ranging from functional genomics to precision medicine and is a conjectured source of substantial heritability. However, unbiased methods to profile GxE genome-wide are nascent and, as we show, cannot accommodate general environment variables, modest sample sizes, heterogeneous noise, and binary traits. To address this gap, we propose a simple, unifying mixed model for gene-environment interaction (GxEMM). In simulations and theory, we show that GxEMM can dramatically improve estimates and eliminate false positives when the assumptions of existing methods fail. We apply GxEMM to a range of human and model organism datasets and find broad evidence of context-specific genetic effects, including GxSex, GxAdversity, and GxDisease interactions across thousands of clinical and molecular phenotypes. Overall, GxEMM is broadly applicable for testing and quantifying polygenic interactions, which can be useful for explaining heritability and invaluable for determining biologically relevant environments.

Alternate JournalAm J Hum Genet
PubMed ID31901249
PubMed Central IDPMC7042488
Grant ListR01 CA227237 / CA / NCI NIH HHS / United States
R03 DE025665 / DE / NIDCR NIH HHS / United States
R01 HG006399 / HG / NHGRI NIH HHS / United States
U01 HG009080 / HG / NHGRI NIH HHS / United States
K25 HL121295 / HL / NHLBI NIH HHS / United States
R01 ES029929 / ES / NIEHS NIH HHS / United States