{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T05:55:04Z","timestamp":1718171704976},"reference-count":80,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2014,1,1]],"date-time":"2014-01-01T00:00:00Z","timestamp":1388534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Haloperidol is an efficacious antipsychotic drug that has serious, unpredictable motor side effects that limit its utility and cause noncompliance in many patients. Using a drug\u2013placebo diallel of the eight founder strains of the Collaborative Cross and their F1 hybrids, we characterized aggregate effects of genetics, sex, parent of origin, and their combinations on haloperidol response. Treating matched pairs of both sexes with drug or placebo, we measured changes in the following: open field activity, inclined screen rigidity, orofacial movements, prepulse inhibition of the acoustic startle response, plasma and brain drug level measurements, and body weight. To understand the genetic architecture of haloperidol response we introduce new statistical methodology linking heritable variation with causal effect of drug treatment. Our new estimators, \u201cdifference of models\u201d and \u201cmultiple-impute matched pairs\u201d, are motivated by the Neyman\u2013Rubin potential outcomes framework and extend our existing Bayesian hierarchical model for the diallel (Lenarcic et al. 2012). Drug-induced rigidity after chronic treatment was affected by mainly additive genetics and parent-of-origin effects (accounting for 28% and 14.8% of the variance), with NZO\/HILtJ and 129S1\/SvlmJ contributions tending to increase this side effect. Locomotor activity after acute treatment, by contrast, was more affected by strain-specific inbreeding (12.8%). In addition to drug response phenotypes, we examined diallel effects on behavior before treatment and found not only effects of additive genetics (10.2\u201353.2%) but also strong effects of epistasis (10.64\u201325.2%). In particular: prepulse inhibition showed additivity and epistasis in about equal proportions (26.1% and 23.7%); there was evidence of nonreciprocal epistasis in pretreatment activity and rigidity; and we estimated a range of effects on body weight that replicate those found in our previous work. Our results provide the first quantitative description of the genetic architecture of haloperidol response in mice and indicate that additive, dominance-like inbreeding and parent-of-origin effects contribute strongly to treatment effect heterogeneity for this drug.<\/jats:p>","DOI":"10.1534\/genetics.113.156901","type":"journal-article","created":{"date-parts":[[2013,11,16]],"date-time":"2013-11-16T03:39:15Z","timestamp":1384573155000},"page":"321-347","source":"Crossref","is-referenced-by-count":30,"title":["Genetics of Adverse Reactions to Haloperidol in a Mouse Diallel: A Drug\u2013Placebo Experiment and Bayesian Causal Analysis"],"prefix":"10.1093","volume":"196","author":[{"given":"James J","family":"Crowley","sequence":"first","affiliation":[{"name":"Department of Genetics , University of North Carolina, Chapel Hill, North Carolina 27599-7264"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunjung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Genetics , University of North Carolina, Chapel Hill, North Carolina 27599-7264"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan B","family":"Lenarcic","sequence":"additional","affiliation":[{"name":"Department of Genetics , University of North Carolina, Chapel Hill, North Carolina 27599-7264"},{"name":"Lineberger Comprehensive Cancer Center , University of North Carolina, Chapel Hill, North Carolina 27599-7264"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corey R","family":"Quackenbush","sequence":"additional","affiliation":[{"name":"Department of Genetics , University of North Carolina, Chapel Hill, North Carolina 27599-7264"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cordelia J","family":"Barrick","sequence":"additional","affiliation":[{"name":"Department of Genetics , University of North Carolina, Chapel Hill, North Carolina 27599-7264"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel E","family":"Adkins","sequence":"additional","affiliation":[{"name":"Center for Biomarker Research and Personalized Medicine , Virginia Commonwealth University, Richmond, Virginia 23298"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ginger S","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Genetics , University of North Carolina, Chapel Hill, North Carolina 27599-7264"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darla R","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Genetics , University of North Carolina, Chapel Hill, North Carolina 27599-7264"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando Pardo-Manuel","family":"de Villena","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center , University of North Carolina, Chapel Hill, North Carolina 27599-7264"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick F","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Genetics , University of North Carolina, Chapel Hill, North Carolina 27599-7264"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Valdar","sequence":"additional","affiliation":[{"name":"Department of Genetics , University of North Carolina, Chapel Hill, North Carolina 27599-7264"},{"name":"Lineberger Comprehensive Cancer Center , University of North Carolina, Chapel Hill, North Carolina 27599-7264"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,1,1]]},"reference":[{"issue":"3","key":"2023030811090744000_","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.biopsych.2009.08.036","article-title":"Genomewide association study of movement-related adverse antipsychotic effects.","volume":"67","author":"\u00c5berg","year":"2010","journal-title":"Biol. 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