Barcoded Bulk QTL mapping reveals highly polygenic and epistatic architecture of complex traits in yeast

Mapping the genetic basis of complex traits is critical to uncovering the
biological mechanisms that underlie disease and other phenotypes.
Genome-wide association studies (GWAS) in humans and quantitative trait
locus (QTL) mapping in model organisms can now explain much of the
observed heritability in many traits, allowing us to predict phenotype
from genotype. However, constraints on power due to statistical
confounders in large GWAS and smaller sample sizes in QTL studies still
limit our ability to resolve numerous small-effect variants, map them to
causal genes, identify pleiotropic effects across multiple traits, and
infer non-additive interactions between loci (epistasis). Here, we
introduce barcoded bulk quantitative trait locus (BB-QTL) mapping, which
allows us to construct, genotype, and phenotype 100,000 offspring of a
budding yeast cross, two orders of magnitude larger than the previous
state of the art. We use this panel to map the genetic basis of eighteen
complex traits, finding that the genetic architecture of these traits
involves hundreds of small-effect loci densely spaced throughout the
genome, many with widespread pleiotropic effects across multiple traits.
Epistasis plays a central role, with thousands of interactions that
provide insight into genetic networks. By dramatically increasing sample
size, BB-QTL mapping demonstrates the potential of natural variants in
high-powered QTL studies to reveal the highly polygenic, pleiotropic, and
epistatic architecture of complex traits.