Abstract
BackgroundThe phenotype of an individual can be affected not only by the individual’s own genotypes, known as direct genetic effects (DGE), but also by genotypes of interacting partners, indirect genetic effects (IGE). IGE have been detected using polygenic models in multiple species, including laboratory mice and humans. However, the underlying mechanisms remain largely unknown. Genome-wide association studies of IGE (igeGWAS) can point to IGE genes, but have not yet been applied to non-familial IGE arising from “peers” and affecting biomedical phenotypes. In addition, the extent to which igeGWAS will identify loci not identified by dgeGWAS remains an open question. Finally, findings from igeGWAS have not been confirmed by experimental manipulation.ResultsWe leverage a dataset of 170 behavioral, physiological, and morphological phenotypes measured in 1812 genetically heterogeneous laboratory mice to study IGE arising between same-sex, adult, unrelated mice housed in the same cage. We develop and apply methods for igeGWAS in this context and identify 24 significant IGE loci for 17 phenotypes (FDR < 10%). We observe no overlap between IGE loci and DGE loci for the same phenotype, which is consistent with the moderate genetic correlations between DGE and IGE for the same phenotype estimated using polygenic models. Finally, we fine-map seven significant IGE loci to individual genes and find supportive evidence in an experiment with a knockout model that Epha4 gives rise to IGE on stress-coping strategy and wound healing.ConclusionsOur results demonstrate the potential for igeGWAS to identify IGE genes and shed light into the mechanisms of peer influence.
Highlights
The phenotype of an individual can be affected by the individual’s own genotypes, known as direct genetic effects (DGE), and by genotypes of interacting partners, indirect genetic effects (IGE)
We identified further reason why dgeGWAS and igeGWAS might identify different loci: using simulations to identify key parameters determining the power of igeGWAS, we found that both the number of cage mates and the mode of aggregation across cage mates are important, in addition to the parameters determining the power of dgeGWAS, namely minor allele frequency (MAF) and allelic effect (Additional file 2: Fig. S4)
This finding was of particular interest because the Epha4 locus was among the three most significant IGE loci for wound healing and because IGE on wound healing seem to be ubiquitous in laboratory mice: we have found a significant aggregate contribution of IGE to rate of healing from an ear punch in all three mouse populations we have looked at to date
Summary
The phenotype of an individual can be affected by the individual’s own genotypes, known as direct genetic effects (DGE), and by genotypes of interacting partners, indirect genetic effects (IGE). The genome-wide association study of IGE (igeGWAS) has been proposed as a strategy to identify individual genetic loci underlying IGE [5, 7, 8, 11, 31,32,33,34,35]. IgeGWAS has only been applied in limited settings: in particular, it has not been used to study non-familial IGE from peers affecting biomedical phenotypes, despite growing evidence from polygenic models in laboratory mice [9] and in humans [25, 26] that such effects are important. The results of igeGWAS have not yet been translated into experimentally validated genes causing IGE
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