Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia.
OBJECTIVE
Neuroleptic-induced tardive dyskinesia (TD) is an involuntary movement disorder that develops in patients who have undergone long-term treatment with antipsychotic medications, and its etiology is unclear. In this study, a genome-wide association screening was done to identify the pathway(s) in which genetic variations influence susceptibility to neuroleptic-induced TD.


METHODS
Screening with Sentrix Human-1 Genotyping BeadChip (Illumina, San Diego, California, USA) was done for 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD. A total of 40 573 single nucleotide polymorphisms that were not in linkage disequilibrium with each other and were located in the exonic and intronic regions of 13 307 genes were analyzed. After gene-based corrections, P values for allelic associations were subjected to canonical pathway-based analyses with Ingenuity Pathway Analysis software (Ingenuity Systems, Inc., Redwood City, California, USA).


RESULTS
Eight genes (ABAT, ALDH9A1, GABRA3, GABRA4, GABRB2, GABRAG3, GPHN, and SLC6A11) contained polymorphisms with gene-based corrected allelic P values of less than 0.05. They were aggregated significantly in 33 genes belonging to the gamma-aminobutyric acid (GABA) receptor signaling pathway (P=0.00007, corrected P=0.01). Associations were replicated in an independent sample of 36 patients with TD and 136 patients without TD for polymorphisms in SLC6A11 (GABA transporter 3) (P=0.0004 in the total sample), GABRB2 (beta-2 subunit of GABA-A receptor) (P=0.00007 in the total sample), and GABRG3 (gamma-3 subunit of GABA-A receptor) (P=0.0006 in the total sample).


CONCLUSIONS
The results suggest that the GABA receptor signaling pathway may be involved in genetic susceptibility to treatment-resistant TD, at least in a subgroup of Japanese patients with schizophrenia. The present results suggest that benzodiazepines may be considered as possible treatment option for TD.
Inada
Toshiya
T
Seiwa Hospital, Institute of Neuropsychiatry, Benten-cho 91, Shinjuku-ku, Tokyo, Japan. han91010@rio.odn.ne.jp
Koga
Minori
M
Ishiguro
Hiroki
H
Horiuchi
Yasue
Y
Syu
Aoi
A
Yoshio
Takashi
T
Takahashi
Nagahide
N
Ozaki
Norio
N
Arinami
Tadao
T
D014150:Antipsychotic Agents / Q000009:adverse effects; D004409:Dyskinesia, Drug-Induced / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018079:Receptors, GABA / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D014150:Antipsychotic Agents; D018079:Receptors, GABA