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Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

ABSTRACT: Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes (CD38, GPNMB, RAB29, TMEM175, TTC19) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD.

SUBMITTER: Shi JJ

PROVIDER: S-EPMC10866412 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Shi Jing-Jing JJ Mao Cheng-Yuan CY Guo Ya-Zhou YZ Fan Yu Y Hao Xiao-Yan XY Li Shuang-Jie SJ Tian Jie J Hu Zheng-Wei ZW Li Meng-Jie MJ Li Jia-Di JD Ma Dong-Rui DR Guo Meng-Nan MN Zuo Chun-Yan CY Liang Yuan-Yuan YY Xu Yu-Ming YM Yang Jian J Shi Chang-He CH

Aging 20240117 2

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and ...[more]

PMID: 38240717

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Project description:Abstract Vertigo is a leading symptom of various peripheral and central vestibular disorders. Although genome-wide association studies (GWASs) have identified multiple risk variants for vertigo, how these risk variants contribute to the risk of vertigo remains unknown. Discovery proteome-wide association study (PWAS) was first performed by integrating the protein quantitative trait loci from the dorsolateral prefrontal cortex (DLPFC) in the Banner Sun Health Research Institute dataset (n = 152) and GWAS summary of vertigo (n = 942 613), followed by replication PWAS using the protein quantitative trait loci from the DLPFC in Religious Orders Study or the Rush Memory and Aging Project dataset (n = 376). Transcriptome-wide association studies (TWASs) were then performed by integrating the same GWAS datasets of vertigo (n = 942 613) with mRNA expression reference from human fetal brain, and DLPFC. Chemical-related gene set enrichment analysis (GSEA) and Gene ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were finally conducted to further reveal the pathogenesis of vertigo. Permutation-based empirical P values were calculated in PWAS, TWAS, and GSEA. By integrating the GWAS of vertigo and two independent brain proteomes from human DLPFC, three genes were identified to genetically regulate protein abundance levels in vertigo, and were not previously implicated by GWAS, including MTERFD2 (PBanner = 0.045, PROSMAP = 0.031), MGST1 (PBanner = 0.014, PROSMAP = 0.018), and RAB3B (PBanner = 0.045, PROSMAP = 0.035). Compared with TWAS results, we identified overlapping genes RAB3B (PTWAS = 0.017) and MTERFD2 (PTWAS = 0.003) that showed significant associations with vertigo at both proteome-wide and transcriptome-wide levels. Chemical-related GSEA identified multiple chemicals that might be associated with vertigo, such as nickel (P = 0.007), glycidamide (P = 0.005), and proanthocyanidins (P = 0.015). Our study provides novel clues for understanding the biological mechanism of vertigo, and highlights several possible risks and therapeutic chemicals for vertigo. Cheng et al. performed proteome-wide association studies to identify genes whose cis-regulated protein abundance changes in the human brain were associated with vertigo, followed by chemical-related gene set enrichment analysis. They provide novel genes (MTERFD2, MGST1, and RAB3B) into the pathogenesis of vertigo, and highlight promising chemicals for further therapeutics research. Graphical Abstract Graphical abstract

Dataset Information

Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Publications

Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Similar Datasets

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