TY - JOUR
T1 - Genomewide Association Study of Movement-Related Adverse Antipsychotic Effects
AU - Åberg, Karolina
AU - Adkins, Daniel E.
AU - Bukszár, József
AU - Webb, Bradley T.
AU - Caroff, Stanley N.
AU - Miller, Del D.
AU - Sebat, Jonathan
AU - Stroup, Scott
AU - Fanous, Ayman H.
AU - Vladimirov, Vladimir I.
AU - McClay, Joseph L.
AU - Lieberman, Jeffrey A.
AU - Sullivan, Patrick F.
AU - van den Oord, Edwin J.C.G.
N1 - Funding Information:
The Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) project was supported by National Institutes of Mental Health contract N01 MH90001 . Dr. Sullivan was supported by Grant Nos. R01s MH074027 and MH077139 , and Dr. van den Oord was supported by Grant Nos. R01s MH078069 and HG004240 .
Funding Information:
Eli Lilly funded the genomewide association study genotyping done at Perlegen Sciences. Dr. Caroff reports having received research funds from Bristol-Myers Squibb, Ortho-McNeil Neurologics, and Pfizer Inc. and consulting fees from Eli Lilly and Co. Dr. Miller Reports having received consulting fees from Organon Schering Plough, Otsuka Pharmaceuticals, and Hoffmann-La Roche Ltd. Dr. Stroup reports receiving consulting funds from Janssen and Lilly. Dr. Lieberman reports having received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica, Wyeth, Merck, Forest Laboratories, Allon, and Pfizer; he has participated in research, consulting, advisory board, or Data Safety Monitoring Board activities from Chephalon, Eli Lilly, Pfizer, Bioline, Lilly, AstraZeneca, Forest laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Otsuka, Wyeth, and Solvay; and has a patent with Repligen. Dr. Sullivan reports receiving research funding from Eli Lilly in connection with this project. Drs. Åberg, Adkins, Bukszár, Webb, Sebat, Fanous, Vladimirov, McClay, and van den Oord reported no biomedical financial interests or potential conflicts of interest.
PY - 2010/2/1
Y1 - 2010/2/1
N2 - Background: Understanding individual differences in the development of extrapyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment. Methods: We performed genomewide association studies to search for genetic susceptibility to EPS. Our sample consisted of 738 schizophrenia patients, genotyped for 492K single nucleotide polymorphisms (SNPs). We studied three quantitative measures of antipsychotic adverse drug reactions-the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale (AIMS)-as well as a clinical diagnosis of probable tardive dyskinesia. Results: Two SNPs for SAS, rs17022444 and rs2126709 with p = 1.2 × 10-10 and p = 3.8 × 10-7, respectively, and one for AIMS, rs7669317 with p = 7.7 × 10-8, reached genomewide significance (Q value < .1). rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting (Q value < .5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1, which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has Parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia. Conclusions: Although our findings require replication and validation, this study demonstrates the potential of genomewide association studies to discover genes and pathways that mediate adverse effects of antipsychotics.
AB - Background: Understanding individual differences in the development of extrapyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment. Methods: We performed genomewide association studies to search for genetic susceptibility to EPS. Our sample consisted of 738 schizophrenia patients, genotyped for 492K single nucleotide polymorphisms (SNPs). We studied three quantitative measures of antipsychotic adverse drug reactions-the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale (AIMS)-as well as a clinical diagnosis of probable tardive dyskinesia. Results: Two SNPs for SAS, rs17022444 and rs2126709 with p = 1.2 × 10-10 and p = 3.8 × 10-7, respectively, and one for AIMS, rs7669317 with p = 7.7 × 10-8, reached genomewide significance (Q value < .1). rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting (Q value < .5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1, which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has Parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia. Conclusions: Although our findings require replication and validation, this study demonstrates the potential of genomewide association studies to discover genes and pathways that mediate adverse effects of antipsychotics.
KW - Antipsychotic
KW - genomewide association
KW - personalized medicine
KW - pharmacogenetics
KW - schizophrenia
KW - single-nucleotide polymorphism
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U2 - 10.1016/j.biopsych.2009.08.036
DO - 10.1016/j.biopsych.2009.08.036
M3 - Article
C2 - 19875103
AN - SCOPUS:73549122994
SN - 0006-3223
VL - 67
SP - 279
EP - 282
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 3
ER -