Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice

• Published in: Mammalian genome 2012-06, Vol.23 (5-6), p.322-335
• Main Authors: Crowley, James J, Kim, Yunjung, Szatkiewicz, Jin Peng, Pratt, Amanda L, Quackenbush, Corey R, Adkins, Daniel E, van den Oord, Edwin, Bogue, Molly A, Yang, Hyuna, Wang, Wei, Threadgill, David W, de Villena, Fernando Pardo-Manuel, McLeod, Howard L, Sullivan, Patrick F
• Format: Article
• Language: English
• Subjects: adverse effects; Animal Genetics and Genomics; Animal models; Animals; Antipsychotic Agents; Antipsychotic Agents - adverse effects; Basal Ganglia Diseases; Basal Ganglia Diseases - chemically induced; Basal Ganglia Diseases - genetics; Basal Ganglia Diseases - physiopathology; Bioinformatics; Biomedical and Life Sciences; Brain; Cell Biology; chemically induced; Chewing; Chromosome Mapping; Data processing; Dopamine D2 receptors; dyskinesia; Dyskinesia, Drug-Induced; Dyskinesia, Drug-Induced - genetics; Dyskinesia, Drug-Induced - physiopathology; Extrapyramidal system; Female; Gene expression; genes; Genetic analysis; genetic techniques and protocols; genetics; Genome-Wide Association Study; Genomic analysis; genomics; glutamic acid; Glutamic acid receptors; Haloperidol; Human Genetics; Humans; Inbreeding; Life Sciences; loci; Male; mastication; Mice; Mice, Inbred A; Motor Activity; Motor task performance; Movement disorders; Neuroleptics; patients; physiopathology; Polymorphism, Single Nucleotide; receptors; Side effects; Single-nucleotide polymorphism; Tardive dyskinesia
• ISSN: 0938-8990; 1432-1777
• DOI: 10.1007/s00335-011-9385-8

Tardive dyskinesia (TD) is a debilitating, unpredictable, and often irreversible side effect resulting from chronic treatment with typical antipsychotic agents such as haloperidol. TD is characterized by repetitive, involuntary, purposeless movements primarily of the orofacial region. In order to investigate genetic susceptibility to TD, we used a validated mouse model for a systems genetics analysis geared toward detecting genetic predictors of TD in human patients. Phenotypic data from 27 inbred strains chronically treated with haloperidol and phenotyped for vacuous chewing movements were subject to a comprehensive genomic analysis involving 426,493 SNPs, 4,047 CNVs, brain gene expression, along with gene network and bioinformatic analysis. Our results identified ~50 genes that we expect to have high prior probabilities for association with haloperidol-induced TD, most of which have never been tested for association with human TD. Among our top candidates were genes regulating the development of brain motor control regions (Zic4 and Nkx6-1), glutamate receptors (Grin1 and Grin2a), and an indirect target of haloperidol (Drd1a) that has not been studied as well as the direct target, Drd2.