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Establishing gene regulatory networks from Parkinson’s disease risk loci

View ORCID ProfileSophie L. Farrow, View ORCID ProfileWilliam Schierding, View ORCID ProfileSreemol Gokuladhas, View ORCID ProfileEvgeniia Golovina, View ORCID ProfileTayaza Fadason, View ORCID ProfileAntony A. Cooper, View ORCID ProfileJustin M. O’Sullivan
doi: https://doi.org/10.1101/2021.04.08.439080
Sophie L. Farrow
1Liggins Institute, The University of Auckland, Auckland, New Zealand
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William Schierding
1Liggins Institute, The University of Auckland, Auckland, New Zealand
2The Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand
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Sreemol Gokuladhas
1Liggins Institute, The University of Auckland, Auckland, New Zealand
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Evgeniia Golovina
1Liggins Institute, The University of Auckland, Auckland, New Zealand
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Tayaza Fadason
1Liggins Institute, The University of Auckland, Auckland, New Zealand
2The Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand
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Antony A. Cooper
3Australian Parkinson’s Mission, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
4St Vincent’s Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
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  • For correspondence: justin.osullivan@auckland.ac.nz
Justin M. O’Sullivan
1Liggins Institute, The University of Auckland, Auckland, New Zealand
2The Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand
5Brain Research New Zealand, The University of Auckland, Auckland, New Zealand
6MRC Lifecourse Epidemiology Unit, University of Southampton, United Kingdom
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  • For correspondence: justin.osullivan@auckland.ac.nz
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Abstract

The latest meta-analysis of genome wide association studies (GWAS) identified 90 independent single nucleotide polymorphisms (SNPs) across 78 genomic regions associated with Parkinson’s disease (PD), 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 PD-SNPs, we utilised an approach combining spatial (chromosomal conformation capture) and functional (expression quantitative trait loci; eQTL) data. We identified 518 genes subject to regulation by 76 PD-SNPs across 49 tissues, that 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 > 1Mb, or on different chromosomes). Of particular interest is the identification of a novel trans-eQTL-gene connection between rs10847864 and SYNJ1 in the adult brain cortex, highlighting a convergence between familial studies and PD GWAS loci for SYNJ1 (PARK20) for the first time. Furthermore, we identified 16 neuro-development specific eQTL-gene regulatory connections within the foetal cortex, consistent with hypotheses suggesting a neurodevelopmental involvement in the pathogenesis of PD. Through utilising Louvain clustering we extracted nine significant and highly intra-connected 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 PD. Together, our results not only contribute to an overall understanding of the mechanisms and impact of specific combinations of PD-SNPs, but also highlight the potential impact gene regulatory networks may have when elucidating aetiological subtypes of PD.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/sfar956/PDGWAS_regulatorynetworks

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 09, 2021.
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Establishing gene regulatory networks from Parkinson’s disease risk loci
Sophie L. Farrow, William Schierding, Sreemol Gokuladhas, Evgeniia Golovina, Tayaza Fadason, Antony A. Cooper, Justin M. O’Sullivan
bioRxiv 2021.04.08.439080; doi: https://doi.org/10.1101/2021.04.08.439080
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Establishing gene regulatory networks from Parkinson’s disease risk loci
Sophie L. Farrow, William Schierding, Sreemol Gokuladhas, Evgeniia Golovina, Tayaza Fadason, Antony A. Cooper, Justin M. O’Sullivan
bioRxiv 2021.04.08.439080; doi: https://doi.org/10.1101/2021.04.08.439080

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