Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice.
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.
Department of Genetics, University of North Carolina, Genomic Medicine Building, CB#7264, Chapel Hill, NC 27599-7264, USA. crowley@unc.edu
James J
JJ
Crowley
Yunjung
Y
Kim
Jin Peng
JP
Szatkiewicz
Amanda L
AL
Pratt
Corey R
CR
Quackenbush
Daniel E
DE
Adkins
Edwin
E
van den Oord
Molly A
MA
Bogue
Hyuna
H
Yang
Wei
W
Wang
David W
DW
Threadgill
Fernando Pardo-Manuel
FP
de Villena
Howard L
HL
McLeod
Patrick F
PF
Sullivan
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D002874:Chromosome Mapping; D004409:Dyskinesia, Drug-Induced / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D009043:Motor Activity; D020641:Polymorphism, Single Nucleotide
D014150:Antipsychotic Agents