Dissecting indirect genetic effects from peers in laboratory mice

Autor: Abraham A. Palmer, Binnaz Yalcin, Oliver Stegle, Jérôme Nicod, Amanda M. Barkley-Levenson, Charlotte Montillot, Francesco Paolo Casale, Amelie Baud, Nilgoun Farhadi
Přispěvatelé: European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of California [San Diego] (UC San Diego), University of California (UC), Microsoft Research New England [Cambridge, MA, USA] (MRNE), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), University of Oxford, Genome Biology Unit [Heidelberg, Germany], European Molecular Biology Laboratory [Hinxton], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), The Wellcome Trust Sanger Institute [Cambridge], Dupuis, Christine
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Genome Biology
Genome Biology, 2021, 22 (1), pp.216. ⟨10.1186/s13059-021-02415-x⟩
Genome Biology, Vol 22, Iss 1, Pp 1-21 (2021)
ISSN: 1474-760X
1474-7596
1465-6906
DOI: 10.1186/s13059-021-02415-x⟩
Popis: Background: The 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. Results: We 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. Conclusions: Our results demonstrate the potential for igeGWAS to identify IGE genes and shed light into the mechanisms of peer influence. Funding: AB was supported by a fellowship from the Wellcome Trust (105941/Z/14/Z). This work was partially supported by a pilot grant from NIH (P50DA037844 to AAP). Research in the Stegle lab is supported by core funding from EMBL, the BMBF, the Volkswagen Foundation, and the EU (ERC project DECODE 810296)
Databáze: OpenAIRE
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