Testing Implications of the Omnigenic Model for the Genetic Analysis of Loci Identified through Genome-wide Association.

Organismal phenotypes usually have a quantitative distribution, and their genetic architecture can be studied by genome-wide association (GWA) mapping approaches. In most of such studies, it has become clear that many genes of moderate or small effects contribute to the phenotype. Hence, the attention has turned toward the loci falling below the GWA cut-off, which may contribute to the phenotype through modifier interactions with a set of core genes, as proposed in the omnigenic model. One can thus predict that both moderate effect GWA-derived candidate genes and randomly chosen genes should have a similar likelihood to affect a given phenotype when they are analyzed via gene disruption assays. We have tested this hypothesis by using an automated phenotyping system for Drosophila pupal phenotypes. We first identified candidate genes for pupal length in a GWA based on the Drosophila Genetic Reference Panel (DGRP) and showed that most of these candidate genes are indeed involved in the phenotype. We then randomly chose genes below a GWA significance threshold and found that three-quarters of them had also an effect on the trait with comparable effect sizes as the GWA candidate genes. We further tested the effects of these knockout lines on an independent behavioral pupal trait (pupation site choice) and found that a similar fraction had a significant effect as well. Our data thus confirm the implication that a large number of genes can influence independent quantitative traits.