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Published on: August 28, 2021
Identification of novel proteins associated with movement-related adverse antipsychotic effects by integrating GWAS
Jiqing Li1, Jicheng Pang2, Shucheng Si1
1Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Culture West Road, Jinan, Shandong 250012, China; Healthcare Big Data Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Abstract:
Genome-wide association studies (GWAS) have identified some variants for movement-related adverse antipsychotic effects (MAAE), while how these variants confer MAAE remains unclear. We used the probabilistic Mendelian randomization (PMR) method to identify candidate proteins for MAAE by integrating MAAE GWASs and protein quantitative trait loci (pQTL) data. An independent pQTL data from the Banner project and brain-derived eQTL data were used to perform confirmatory PMR. A total of 56 proteins were identified as candidate targets for MAAE after false discovery rates (FDR) correction, such as GRIN2B, ADRA1A, and PED4B. 12 genes were replicated in the confirmatory PMR, and 18 genes had consistent evidence at the transcript level. Furthermore, we investigated the associations between candidate proteins and the motor symptoms of Parkinson's disease (PD). There were 24, 38, and 10 candidate proteins that were significantly associated with PD, PD motor subtypes, and PD motor progression, respectively. Enrichment analysis identified 34 GO terms and 17 pathways that may be involved in MAAE, such as glutamatergic synapse, glutamate receptor complex, and GABAergic synapse. Our study identified multiple candidate genes and pathways that were associated with MAAE, providing new insights into the biological mechanism of MAAE and targets for further mechanistic and therapeutic studies.
Insights
This study identifies 56 candidate proteins linked to movement-related adverse antipsychotic effects (MAAE) using probabilistic Mendelian randomization. These findings offer new biological insights and potential therapeutic targets for MAAE.
Area of Science:
- Neuroscience
- Pharmacogenomics
- Genetics
Background:
- Genome-wide association studies (GWAS) have identified genetic variants associated with movement-related adverse antipsychotic effects (MAAE).
- The biological mechanisms by which these variants confer MAAE remain largely unknown.
- Understanding these mechanisms is crucial for developing safer antipsychotic treatments.
Purpose of the Study:
- To identify candidate proteins and biological pathways involved in MAAE using a genetic approach.
- To explore the overlap between MAAE candidate proteins and Parkinson's disease (PD) motor symptoms.
- To provide novel targets for mechanistic and therapeutic research into MAAE.
Main Methods:
- Probabilistic Mendelian randomization (PMR) was employed to integrate MAAE GWAS data with protein quantitative trait loci (pQTL) data.
- Confirmatory PMR was performed using independent pQTL and brain-derived eQTL data.
- Associations between identified candidate proteins and Parkinson's disease motor symptoms were investigated. Enrichment analysis was conducted for Gene Ontology (GO) terms and pathways.
Main Results:
- A total of 56 candidate proteins for MAAE were identified after FDR correction, including GRIN2B, ADRA1A, and PED4B.
- Replication in confirmatory analyses yielded 12 genes, with 18 showing consistent transcript-level evidence.
- Significant associations were found between candidate proteins and PD (24 proteins), PD motor subtypes (38 proteins), and PD motor progression (10 proteins).
- Enrichment analysis highlighted 34 GO terms and 17 pathways, such as glutamatergic synapse and GABAergic synapse, potentially involved in MAAE.
Conclusions:
- This study successfully identified multiple candidate genes and pathways implicated in MAAE.
- The findings provide valuable insights into the biological underpinnings of MAAE.
- The identified targets warrant further investigation for potential therapeutic interventions for MAAE.
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