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Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets

IMPORTANCE: Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key...

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Autores principales: Kia, Demis A., Zhang, David, Guelfi, Sebastian, Manzoni, Claudia, Hubbard, Leon, Reynolds, Regina H., Botía, Juan, Ryten, Mina, Ferrari, Raffaele, Lewis, Patrick A., Williams, Nigel, Trabzuni, Daniah, Hardy, John, Wood, Nicholas W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Medical Association 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851759/
https://www.ncbi.nlm.nih.gov/pubmed/33523105
http://dx.doi.org/10.1001/jamaneurol.2020.5257
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author Kia, Demis A.
Zhang, David
Guelfi, Sebastian
Manzoni, Claudia
Hubbard, Leon
Reynolds, Regina H.
Botía, Juan
Ryten, Mina
Ferrari, Raffaele
Lewis, Patrick A.
Williams, Nigel
Trabzuni, Daniah
Hardy, John
Wood, Nicholas W.
author_facet Kia, Demis A.
Zhang, David
Guelfi, Sebastian
Manzoni, Claudia
Hubbard, Leon
Reynolds, Regina H.
Botía, Juan
Ryten, Mina
Ferrari, Raffaele
Lewis, Patrick A.
Williams, Nigel
Trabzuni, Daniah
Hardy, John
Wood, Nicholas W.
author_sort Kia, Demis A.
collection PubMed
description IMPORTANCE: Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. OBJECTIVE: To investigate what genes and genomic processes underlie the risk of sporadic PD. DESIGN AND SETTING: This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. MAIN OUTCOMES AND MEASURES: It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. RESULTS: Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. CONCLUSIONS AND RELEVANCE: Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies.
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spelling pubmed-78517592021-02-11 Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets Kia, Demis A. Zhang, David Guelfi, Sebastian Manzoni, Claudia Hubbard, Leon Reynolds, Regina H. Botía, Juan Ryten, Mina Ferrari, Raffaele Lewis, Patrick A. Williams, Nigel Trabzuni, Daniah Hardy, John Wood, Nicholas W. JAMA Neurol Original Investigation IMPORTANCE: Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. OBJECTIVE: To investigate what genes and genomic processes underlie the risk of sporadic PD. DESIGN AND SETTING: This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. MAIN OUTCOMES AND MEASURES: It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. RESULTS: Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. CONCLUSIONS AND RELEVANCE: Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies. American Medical Association 2021-02-01 2021-04 /pmc/articles/PMC7851759/ /pubmed/33523105 http://dx.doi.org/10.1001/jamaneurol.2020.5257 Text en Copyright 2021 Kia DA et al. JAMA Neurology. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the CC-BY License.
spellingShingle Original Investigation
Kia, Demis A.
Zhang, David
Guelfi, Sebastian
Manzoni, Claudia
Hubbard, Leon
Reynolds, Regina H.
Botía, Juan
Ryten, Mina
Ferrari, Raffaele
Lewis, Patrick A.
Williams, Nigel
Trabzuni, Daniah
Hardy, John
Wood, Nicholas W.
Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets
title Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets
title_full Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets
title_fullStr Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets
title_full_unstemmed Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets
title_short Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets
title_sort identification of candidate parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851759/
https://www.ncbi.nlm.nih.gov/pubmed/33523105
http://dx.doi.org/10.1001/jamaneurol.2020.5257
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