Genomewide Association Study of Movement-Related Adverse Antipsychotic Effects
Open accessAbstract
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 x 10(-10) and p = 3.8 x 10(-7), respectively, and one for AIMS, rs7669317 with p = 7.7 x 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.
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Exploratory analyses show two differentially methylated sites significantly associated with both only cannabis use and cannabis with tobacco, which are within the MARC2 gene and within the CUX1 gene.
“Moreover, these exploratory analyses show two differentially methylated sites significantly associated with both only CU and cannabis with tobacco, which are within the MARC2 gene. The latter previously linked to adverse effects to antipsychotics in schizophrenia (Åberg et al., 2010) and within the CUX1 gene which is involved in neuronal development (Platzer et al., 2018).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Åberg et al., 2010
The citation is attached to the claim that MARC2 was previously linked to antipsychotic adverse effects in schizophrenia. The Results report genetic associations with movement-related adverse effects, including a significant variant in ZNF202, but the passages found by searching for MARC2 and related gene names do not mention MARC2. The cited paper therefore does not establish the specific MARC2 link in our copy. (LLM, conf=0.72)
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“The latter previously linked to adverse effects to antipsychotics in schizophrenia (Åberg et al., 2010) and within the CUX1 gene which is involved in neuronal development (Platzer et al., 2018).”
BackgroundGenome-wide DNA methylation analysis of heavy cannabis exposure in a New Zealand longitudinal cohort
Osborne, A. J., Pearson, J. F., Noble, A. J., Gemmell, N. J., Horwood, L. J., Boden, J. M., Benton, M. C., Macartney-Coxson, D. P., & Kennedy, M. A. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0800-3 · Cited by 47 · see citing works
- Authors
- Åberg, K., Adkins, D. E., Bukszár, J., Webb, B. T., Caroff, S. N., Miller, D. D., Sebat, J., Stroup, S., Fanous, A. H., Vladimirov, V. I., McClay, J. L., Lieberman, J. A., Sullivan, P. F., & van den Oord, E. J. C. G.
- Affiliations
- Virginia Commonwealth University (US)
- Philadelphia VA Medical Center (US)
- University of Iowa (US)
- Cold Spring Harbor Laboratory (US)
- Columbia University (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Åberg, Karolina
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 67
- Issue
- 3
- Pages
- 279-282
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3388725
- OpenAlex
- W2094991340
- Cited by
- 130
- References
- 1
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 14 · 2015: 7 · 2014: 9 · 2013: 11 · 2012: 15
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Institutes of Mental Health (MH90001, MH074027, MH077139, MH078069, HG004240)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- antipsychotic adverse effects, extrapyramidal symptoms, schizophrenia, genetic susceptibility, parkinsonism, akathisia, tardive dyskinesia, abnormal involuntary movements, PLP1, Pelizaeus-Merzbacher disease, Simpson-Angus Scale, Abnormal Involuntary Movement Scale
- MeSH terms
- Adult, Female, Humans, Male, Middle Aged, Movement Disorders, Psychiatric Status Rating Scales, Repressor Proteins, RNA, Messenger, Schizophrenia, Antipsychotic Agents, Myelin Proteolipid Protein, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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