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Establishing gene regulatory networks from Parkinson’s disease risk loci

The latest meta-analysis of genome-wide association studies identified 90 independent variants across 78 genomic regions associated with Parkinson’s disease, yet the mechanisms by which these variants influence the development of the disease remains largely elusive. To establish the functional gene...

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Autores principales: Farrow, Sophie L, Schierding, William, Gokuladhas, Sreemol, Golovina, Evgeniia, Fadason, Tayaza, Cooper, Antony A, O’Sullivan, Justin M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9373962/
https://www.ncbi.nlm.nih.gov/pubmed/35094046
http://dx.doi.org/10.1093/brain/awac022
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author Farrow, Sophie L
Schierding, William
Gokuladhas, Sreemol
Golovina, Evgeniia
Fadason, Tayaza
Cooper, Antony A
O’Sullivan, Justin M
author_facet Farrow, Sophie L
Schierding, William
Gokuladhas, Sreemol
Golovina, Evgeniia
Fadason, Tayaza
Cooper, Antony A
O’Sullivan, Justin M
author_sort Farrow, Sophie L
collection PubMed
description The latest meta-analysis of genome-wide association studies identified 90 independent variants across 78 genomic regions associated with Parkinson’s disease, yet the mechanisms by which these variants influence the development of the disease remains largely elusive. To establish the functional gene regulatory networks associated with Parkinson’s disease risk variants, we utilized an approach combining spatial (chromosomal conformation capture) and functional (expression quantitative trait loci) data. We identified 518 genes subject to regulation by 76 Parkinson’s variants across 49 tissues, whicih encompass 36 peripheral and 13 CNS tissues. Notably, one-third of these genes were regulated via trans-acting mechanisms (distal; risk locus-gene separated by >1 Mb, or on different chromosomes). Of particular interest is the identification of a novel trans-expression quantitative trait loci–gene connection between rs10847864 and SYNJ1 in the adult brain cortex, highlighting a convergence between familial studies and Parkinson’s disease genome-wide association studies loci for SYNJ1 (PARK20) for the first time. Furthermore, we identified 16 neurodevelopment-specific expression quantitative trait loci–gene regulatory connections within the foetal cortex, consistent with hypotheses suggesting a neurodevelopmental involvement in the pathogenesis of Parkinson’s disease. Through utilizing Louvain clustering we extracted nine significant and highly intraconnected clusters within the entire gene regulatory network. The nine clusters are enriched for specific biological processes and pathways, some of which have not previously been associated with Parkinson’s disease. Together, our results not only contribute to an overall understanding of the mechanisms and impact of specific combinations of Parkinson’s disease variants, but also highlight the potential impact gene regulatory networks may have when elucidating aetiological subtypes of Parkinson’s disease.
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spelling pubmed-93739622022-08-15 Establishing gene regulatory networks from Parkinson’s disease risk loci Farrow, Sophie L Schierding, William Gokuladhas, Sreemol Golovina, Evgeniia Fadason, Tayaza Cooper, Antony A O’Sullivan, Justin M Brain Original Article The latest meta-analysis of genome-wide association studies identified 90 independent variants across 78 genomic regions associated with Parkinson’s disease, yet the mechanisms by which these variants influence the development of the disease remains largely elusive. To establish the functional gene regulatory networks associated with Parkinson’s disease risk variants, we utilized an approach combining spatial (chromosomal conformation capture) and functional (expression quantitative trait loci) data. We identified 518 genes subject to regulation by 76 Parkinson’s variants across 49 tissues, whicih encompass 36 peripheral and 13 CNS tissues. Notably, one-third of these genes were regulated via trans-acting mechanisms (distal; risk locus-gene separated by >1 Mb, or on different chromosomes). Of particular interest is the identification of a novel trans-expression quantitative trait loci–gene connection between rs10847864 and SYNJ1 in the adult brain cortex, highlighting a convergence between familial studies and Parkinson’s disease genome-wide association studies loci for SYNJ1 (PARK20) for the first time. Furthermore, we identified 16 neurodevelopment-specific expression quantitative trait loci–gene regulatory connections within the foetal cortex, consistent with hypotheses suggesting a neurodevelopmental involvement in the pathogenesis of Parkinson’s disease. Through utilizing Louvain clustering we extracted nine significant and highly intraconnected clusters within the entire gene regulatory network. The nine clusters are enriched for specific biological processes and pathways, some of which have not previously been associated with Parkinson’s disease. Together, our results not only contribute to an overall understanding of the mechanisms and impact of specific combinations of Parkinson’s disease variants, but also highlight the potential impact gene regulatory networks may have when elucidating aetiological subtypes of Parkinson’s disease. Oxford University Press 2022-01-30 /pmc/articles/PMC9373962/ /pubmed/35094046 http://dx.doi.org/10.1093/brain/awac022 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Article
Farrow, Sophie L
Schierding, William
Gokuladhas, Sreemol
Golovina, Evgeniia
Fadason, Tayaza
Cooper, Antony A
O’Sullivan, Justin M
Establishing gene regulatory networks from Parkinson’s disease risk loci
title Establishing gene regulatory networks from Parkinson’s disease risk loci
title_full Establishing gene regulatory networks from Parkinson’s disease risk loci
title_fullStr Establishing gene regulatory networks from Parkinson’s disease risk loci
title_full_unstemmed Establishing gene regulatory networks from Parkinson’s disease risk loci
title_short Establishing gene regulatory networks from Parkinson’s disease risk loci
title_sort establishing gene regulatory networks from parkinson’s disease risk loci
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9373962/
https://www.ncbi.nlm.nih.gov/pubmed/35094046
http://dx.doi.org/10.1093/brain/awac022
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