{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:16:41Z","timestamp":1790709401774,"version":"4.1.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T00:00:00Z","timestamp":1660694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TE622\/4\u20132 BE3703\/8\u20132"],"award-info":[{"award-number":["TE622\/4\u20132 BE3703\/8\u20132"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Feather pecking in chickens is a damaging behavior, seriously impacting animal welfare and leading to economic losses. Feather pecking is a complex trait, which is partly under genetic control. Different hypotheses have been proposed to explain the etiology of feather pecking and notably, several studies have identified similarities between feather pecking and human mental disorders such as obsessive-compulsive disorder and schizophrenia. This study uses transcriptomic and phenotypic data from 167 chickens to map expression quantitative trait loci and to identify regulatory genes with a significant effect on this behavioral disorder using an association weight matrix approach. From 70 of the analyzed differentially expressed genes, 11,790 genome wide significantly associated variants were detected, of which 23 showed multiple associations (\u226515). These were located in proximity to a number of genes, which are transcription regulators involved in chromatin binding, nucleic acid metabolism, protein translation and putative regulatory RNAs. The association weight matrix identified 36 genes and the two transcription factors: <jats:italic>SP6<\/jats:italic> (synonym: <jats:italic>KLF14<\/jats:italic>) and <jats:italic>ENSGALG00000042129<\/jats:italic> (synonym: <jats:italic>CHTOP<\/jats:italic>) as the most significant, with an enrichment of KLF14 binding sites being detectable in 40 differentially expressed genes. This indicates that differential expression between animals showing high and low levels of feather pecking was significantly associated with a genetic variant in proximity to <jats:italic>KLF14<\/jats:italic>. This multiallelic variant was located 652 bp downstream of <jats:italic>KLF14<\/jats:italic> and is a deletion of 1-3 bp. We propose that a deletion downstream of the transcription factor <jats:italic>KLF14<\/jats:italic> has a negative impact on the level of T cells in the developing brain of high feather pecking chickens, which leads to developmental and behavioral abnormalities. The lack of CD4 T cells and gamma-Aminobutyric acid (GABA) receptors are important factors for the increased propensity of laying hens to perform feather pecking. As such, <jats:italic>KLF14<\/jats:italic> is a clear candidate regulator for the expression of genes involved in the pathogenic development. By further elucidating the regulatory pathways involved in feather pecking we hope to take significant steps forward in explaining and understanding other mental disorders, not just in chickens.<\/jats:p>","DOI":"10.3389\/fgene.2022.969752","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T08:03:30Z","timestamp":1660723410000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["eQTL analysis of laying hens divergently selected for feather pecking identifies KLF14 as a potential key regulator for this behavioral disorder"],"prefix":"10.3389","volume":"13","author":[{"given":"Alexander Charles","family":"Mott","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Mott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siegfried","family":"Preu\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rn","family":"Bennewitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Tetens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Falker-Gieske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1080\/00071667508416212","article-title":"Feather pecking and cannibalism in a caged layer flock","volume":"16","author":"Allen","year":"1975","journal-title":"Br. Poult. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1079\/WPS19910013","article-title":"Welfare of laying hens in cages and alternative systems: Environmental, physical and behavioural aspects","volume":"47","author":"Appleby","year":"1991","journal-title":"World's. Poult. Sci. J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"103846","DOI":"10.1016\/j.ejmg.2020.103846","article-title":"Whole exome sequencing identified a novel nonsense INPP4A mutation in a family with intellectual disability","volume":"63","author":"Banihashemi","year":"2020","journal-title":"Eur. J. Med. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"810","DOI":"10.3382\/ps.2013-03638","article-title":"Genetic parameters for feather pecking and aggressive behavior in a large F2-cross of laying hens using generalized linear mixed models","volume":"93","author":"Bennewitz","year":"2014","journal-title":"Poult. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/0168-1591(86)90040-7","article-title":"Feather-pecking in poultry: Its relation with ground-pecking","volume":"16","author":"Blokhuis","year":"1986","journal-title":"Appl. Anim. Behav. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.ajhg.2018.07.015","article-title":"A one-penny imputed genome from next-generation reference panels","volume":"103","author":"Browning","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1093\/ps\/82.8.1215","article-title":"Mapping quantitative trait loci affecting feather pecking behavior and stress response in laying hens","volume":"82","author":"Buitenhuis","year":"2003","journal-title":"Poult. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"D165","DOI":"10.1093\/nar\/gkab1113","article-title":"Jaspar 2022: the 9th release of the open-access database of transcription factor binding profiles","volume":"50","author":"Castro-Mondragon","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3389\/fpsyt.2016.00061","article-title":"GABA system in schizophrenia and mood disorders: A mini review on third-generation imaging studies","volume":"7","author":"Chiapponi","year":"2016","journal-title":"Front. Psychiatry"},{"key":"B10","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1080\/00071668908417172","article-title":"Behavioural consequences of partial beak amputation (beak trimming) in poultry","volume":"30","author":"Duncan","year":"1989","journal-title":"Br. Poult. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1074\/mcp.M113.035600","article-title":"Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics","volume":"13","author":"Fagerberg","year":"2014","journal-title":"Mol. Cell. Proteomics."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1007\/s11033-021-07111-4","article-title":"The light response in chickens divergently selected for feather pecking behavior reveals mechanistic insights towards psychiatric disorders","volume":"49","author":"Falker-Gieske","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1186\/s12863-020-00920-9","article-title":"Meta-analyses of genome wide association studies in lines of laying hens divergently selected for feather pecking using imputed sequence level genotypes","volume":"21","author":"Falker-Gieske","year":"","journal-title":"BMC Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1186\/s12864-020-07002-1","article-title":"Analysis of the brain transcriptome in lines of laying hens divergently selected for feather pecking","volume":"21","author":"Falker-Gieske","year":"","journal-title":"BMC Genomics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1074\/mcp.M112.017194","article-title":"Five friends of methylated chromatin target of protein-arginine-methyltransferaseprmt-1 (chtop), a complex linking arginine methylation to desumoylation","volume":"11","author":"Fanis","year":"2012","journal-title":"Mol. Cell. Proteomics."},{"key":"B16","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.ajhg.2019.05.003","article-title":"Pathogenic variants in NUP214 cause \"plugged\" nuclear pore channels and acute febrile encephalopathy","volume":"105","author":"Fichtman","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/mp.2014.63","article-title":"Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia","volume":"20","author":"F\u00f6cking","year":"2015","journal-title":"Mol. Psychiatry"},{"key":"B18","doi-asserted-by":"publisher","first-page":"eaat8127","DOI":"10.1126\/science.aat8127","article-title":"Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder","volume":"362","author":"Gandal","year":"2018","journal-title":"Science"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e0215495","DOI":"10.1371\/journal.pone.0215495","article-title":"CiiiDER: a tool for predicting and analysing transcription factor binding sites","volume":"14","author":"Gearing","year":"2019","journal-title":"PLoS ONE"},{"key":"B20","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/0168-1591(90)90014-5","article-title":"Behavioural evidence for persistent pain following partial beak amputation in chickens","volume":"27","author":"Gentle","year":"1990","journal-title":"Appl. Anim. Behav. Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1016\/j.tig.2008.06.001","article-title":"Revealing the architecture of gene regulation: The promise of eQTL studies","volume":"24","author":"Gilad","year":"2008","journal-title":"Trends Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s12711-015-0154-0","article-title":"Genetic parameters and signatures of selection in two divergent laying hen lines selected for feather pecking behaviour","volume":"47","author":"Grams","year":"2015","journal-title":"Genet. Sel. Evol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.neubiorev.2018.07.007","article-title":"Where in the serotonergic system does it go wrong? Unravelling the route by which the serotonergic system affects feather pecking in chickens","volume":"95","author":"Haas","year":"2018","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e58430","DOI":"10.7554\/eLife.58430","article-title":"DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia","volume":"10","author":"Hannon","year":"2021","journal-title":"Elife"},{"key":"B25","volume-title":"Feather pecking in pheasants: An ethological approach to the problem","author":"Hoffmeyer","year":"1969"},{"key":"B26","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1006\/anbe.1996.0506","article-title":"Feather pecking in domestic chicks: Its relation to dustbathing and foraging","volume":"54","author":"Huber-eicher","year":"1997","journal-title":"Anim. Behav."},{"key":"B27","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1080\/00071667208415981","article-title":"The influence of strain and environmental factors upon feather pecking and cannibalism in fowls","volume":"13","author":"Hughes","year":"1972","journal-title":"Br. Poult. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s10519-019-09971-w","article-title":"A novel model to explain extreme feather pecking behavior in laying hens","volume":"50","author":"Iffland","year":"","journal-title":"Behav. Genet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"262","DOI":"10.3390\/ani10020262","article-title":"Genomewide mapping of selection signatures and genes for extreme feather pecking in two divergently selected laying hen lines","volume":"10","author":"Iffland","year":"","journal-title":"Animals."},{"key":"B30","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1534\/genetics.115.179010","article-title":"Genetical Genomics of behavior: a novel chicken genomic model for anxiety behavior","volume":"202","author":"Johnsson","year":"2016","journal-title":"Genetics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.schres.2015.06.002","article-title":"Abnormal N-acetylglucosaminyltransferase expression in prefrontal cortex in schizophrenia","volume":"166","author":"Kippe","year":"2015","journal-title":"Schizophr. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e0182103","DOI":"10.1371\/journal.pone.0182103","article-title":"Divergent selection on home pen locomotor activity in a chicken model: selection program, genetic parameters and direct response on activity and body weight","volume":"12","author":"Kjaer","year":"2017","journal-title":"PLoS ONE"},{"key":"B33","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1080\/00071669708417999","article-title":"Feather pecking behaviour in White Leghorns, a genetic study","volume":"38","author":"Kjaer","year":"1997","journal-title":"Br. Poult. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"4457","DOI":"10.1046\/j.1460-9568.1999.00887.x","article-title":"Short communication: altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice)","volume":"11","author":"Knuesel","year":"1999","journal-title":"Eur. J. Neurosci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.schres.2015.02.005","article-title":"Altered prefrontal cortical MARCKS and PPP1R9A mRNA expression in schizophrenia and bipolar disorder","volume":"164","author":"Konopaske","year":"2015","journal-title":"Schizophr. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41525-018-0075-2","article-title":"Both rare and common genetic variants contribute to autism in the Faroe Islands","volume":"4","author":"Leblond","year":"2019","journal-title":"NPJ Genom. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"725301","DOI":"10.3389\/fcell.2021.725301","article-title":"Protein arginine methyltransferase 5 functions via interacting proteins","volume":"9","author":"Liang","year":"2021","journal-title":"Front. Cell. Dev. Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s12711-017-0287-4","article-title":"A genome-wide association study in a large F2-cross of laying hens reveals novel genomic regions associated with feather pecking and aggressive pecking behavior","volume":"49","author":"Lutz","year":"2017","journal-title":"Genet. Sel. Evol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"D222","DOI":"10.1093\/nar\/gku1221","article-title":"Cdd: NCBI's conserved domain database","volume":"43","author":"Marchler-Bauer","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.lfs.2016.12.015","article-title":"Acetylcholine released from T cells regulates intracellular Ca2+, IL-2 secretion and T cell proliferation through nicotinic acetylcholine receptor","volume":"172","author":"Mashimo","year":"2017","journal-title":"Life Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.schres.2015.05.001","article-title":"Metabotropic glutamate receptor 5, and its trafficking molecules norbin and tamalin, are increased in the CA1 hippocampal region of subjects with schizophrenia","volume":"166","author":"Matosin","year":"2015","journal-title":"Schizophr. Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"D183","DOI":"10.1093\/nar\/gkw1138","article-title":"PANTHER version 11: Expanded annotation data from gene ontology and reactome pathways, and data analysis tool enhancements","volume":"45","author":"Mi","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"536","DOI":"10.3382\/ps.2008-00424","article-title":"Does enhancement of specific immune responses predispose laying hens for feather pecking?","volume":"88","author":"Parmentier","year":"2009","journal-title":"Poult. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.cell.2020.06.026","article-title":"Microglia require CD4 T cells to complete the fetal-to-adult transition","volume":"182","author":"Pasciuto","year":"2020","journal-title":"Cell."},{"key":"B45","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1534\/g3.119.400798","article-title":"Improving imputation quality in BEAGLE for crop and livestock data","volume":"10","author":"Pook","year":"2020","journal-title":"G3 (Bethesda)"},{"key":"B46","doi-asserted-by":"publisher","first-page":"2491","DOI":"10.1093\/bioinformatics\/btn482","article-title":"Combining partial correlation and an information theory approach to the reversed engineering of gene co-expression networks","volume":"24","author":"Reverter","year":"2008","journal-title":"Bioinformatics"},{"key":"B47","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/978-1-62703-447-0_20","article-title":"Association weight matrix: a network-based approach towards functional genome-wide association studies","volume":"1019","author":"Reverter","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1093\/ps\/82.6.861","article-title":"Heritability of feather pecking and open-field response of laying hens at two different ages","volume":"82","author":"Rodenburg","year":"2003","journal-title":"Poult. Sci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/j.schres.2019.10.032","article-title":"Increased number of T-lymphocytes in post-mortem brain tissue of patients with schizophrenia","volume":"216","author":"Sneeboer","year":"2019","journal-title":"Schizophr. Res."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.1002\/ajmg.a.38654","article-title":"LIPT1 deficiency presenting as early infantile epileptic encephalopathy, leigh disease, and secondary pyruvate dehydrogenase complex deficiency","volume":"176","author":"Stowe","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"B52","doi-asserted-by":"publisher","first-page":"5297","DOI":"10.1038\/s41380-020-01008-7","article-title":"Natural killer cells in first-episode psychosis: an innate immune signature?","volume":"26","author":"Tarantino","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"B53","doi-asserted-by":"publisher","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: the universal protein knowledgebase in 2021","volume":"49","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B54","doi-asserted-by":"publisher","first-page":"112680","DOI":"10.1016\/j.physbeh.2019.112680","article-title":"Chicken lines divergently selected on feather pecking differ in immune characteristics","volume":"212","author":"van der Eijk","year":"2019","journal-title":"Physiol. Behav."},{"key":"B55","doi-asserted-by":"publisher","first-page":"4349","DOI":"10.1182\/blood-2010-03-274399","article-title":"Fetal globin expression is regulated by friend of Prmt1","volume":"116","author":"van Dijk","year":"","journal-title":"Blood"},{"key":"B56","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1128\/MCB.00645-09","article-title":"Friend of Prmt1, a novel chromatin target of protein arginine methyltransferases","volume":"30","author":"van Dijk","year":"","journal-title":"Mol. Cell. Biol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1006\/anbe.1993.1137","article-title":"Feather pecking and chronic fear in groups of red junglefowl: their relations to dustbathing, rearing environment and social status","volume":"45","author":"Vestergaard","year":"1993","journal-title":"Anim. Behav."},{"key":"B58","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1002\/syn.21540","article-title":"A new trick of INPP4A: Decreased expression of INPP4A in patients with temporal lobe epilepsy and pilocarpine-induced rat model","volume":"66","author":"Wang","year":"2012","journal-title":"Synapse"},{"key":"B59","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1017\/S0043933910000644","article-title":"Genetic and physiological factors influencing feather pecking in chickens","volume":"66","author":"Wysocki","year":"2010","journal-title":"World's. Poult. Sci. J."},{"key":"B60","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ajhg.2010.11.011","article-title":"Gcta: a tool for genome-wide complex trait analysis","volume":"88","author":"Yang","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"B61","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1002\/dneu.22795","article-title":"Role of ash1l in turette syndrome and other neurodevelopmental disorders","volume":"81","author":"Zhang","year":"2021","journal-title":"Dev. Neurobiol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.969752\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T08:03:36Z","timestamp":1660723416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.969752\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,17]]},"references-count":61,"alternative-id":["10.3389\/fgene.2022.969752"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.969752","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,17]]},"article-number":"969752"}}