{"doi":"10.1101/2021.08.10.455860","title":"Parent-of-origin effects propagate through networks to shape metabolic traits","abstract":"ABSTRACT Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological diseases. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F 16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these parent-of-origin effects phenomena. We propose that non-imprinted genes can generate complex parent-of-origin effects on metabolic traits through interactions with imprinted genes. Here, we employ data from mouse populations at different levels of intercrossing (F 0 , F 1 , F 2 , F 16 ) of the LG/J and SM/J inbred mouse lines to test this hypothesis. Using multiple populations and incorporating genetic, genomic, and physiological data, we leverage orthogonal evidence to identify networks of genes through which parent-of-origin effects propagate. We identify a network comprised of 3 imprinted and 6 non-imprinted genes that show parent-of-origin effects. This epistatic network forms a nutritional responsive pathway and the genes comprising it jointly serve cellular functions associated with growth. We focus on 2 genes, Nnat and F2r , whose interaction associates with serum glucose levels across generations in high fat-fed females. Single-cell RNAseq reveals that Nnat and F2r are negatively correlated in pre-adipocytes along an adipogenic trajectory, a result that is consistent with our observations in bulk white adipose tissue.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":216752,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9484,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":275081,"name":"Celine L. St. Pierre","orcid":"0000-0001-5465-6601","position":1,"is_corresponding":false},{"id":377720,"name":"Jessica P. Wayhart","orcid":null,"position":2,"is_corresponding":false},{"id":760072,"name":"Yin Li","orcid":"0000-0002-5454-4201","position":3,"is_corresponding":false},{"id":760070,"name":"Larry D. Spears","orcid":"0000-0003-2797-684X","position":4,"is_corresponding":false},{"id":376501,"name":"Mario A Miranda","orcid":"0000-0001-7382-2521","position":5,"is_corresponding":false},{"id":55087,"name":"Caryn Carson","orcid":"0000-0003-2091-3109","position":6,"is_corresponding":false},{"id":262194,"name":"Katsuhiko Funai","orcid":"0000-0003-3802-4756","position":7,"is_corresponding":false},{"id":411617,"name":"James M. Cheverud","orcid":"0000-0001-7651-863X","position":8,"is_corresponding":false},{"id":241850,"name":"Clay F. Semenkovich","orcid":"0000-0003-1163-1871","position":9,"is_corresponding":false},{"id":24492,"name":"Heather A. Lawson","orcid":"0000-0002-3550-5485","position":10,"is_corresponding":false},{"id":376499,"name":"Juan F Macias-Velasco","orcid":"0000-0003-2827-4647","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:15.868165Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}