Tradeoffs in Modeling Context Dependency in Complex Trait Genetics.

Genome-wide association studies have shown surprisingly little evidence for genetic effects on complex traits depending on context (e.g., age, sex, environmental exposures). At the same time, we have learned from the last two decades of GWAS that additive trait variation is often due to small contributions from large parts of the genome. This observation shifted our perspective and sparked a methodological effort to analyze these subtler and harder to interpret associations from throughout the genome together with core genes. Here, we argue through theory and empirical example that a similar shift in the consideration of high polygenicity is an important piece missing from our understanding of context-specificity in complex traits.