Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms

Abstract Genome-wide association studies (GWAS) have identified multiple genetic risk signals for Parkinson’s disease (PD), however translation into underlying biological mechanisms remains scarce. Genomic functional annotations of neurons provide new resources that may be integrated into analyses o...

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Autores principales:	Victoria Berge-Seidl, Lasse Pihlstrøm, Mathias Toft
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ae756f46afd749a8a90e72adbcf8655d
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spelling	oai:doaj.org-article:ae756f46afd749a8a90e72adbcf8655d2021-12-02T12:09:18ZIntegrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms10.1038/s41598-021-83087-22045-2322https://doaj.org/article/ae756f46afd749a8a90e72adbcf8655d2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83087-2https://doaj.org/toc/2045-2322Abstract Genome-wide association studies (GWAS) have identified multiple genetic risk signals for Parkinson’s disease (PD), however translation into underlying biological mechanisms remains scarce. Genomic functional annotations of neurons provide new resources that may be integrated into analyses of GWAS findings. Altered transcription factor binding plays an important role in human diseases. Insight into transcriptional networks involved in PD risk mechanisms may thus improve our understanding of pathogenesis. We analysed overlap between genome-wide association signals in PD and open chromatin in neurons across multiple brain regions, finding a significant enrichment in the superior temporal cortex. The involvement of transcriptional networks was explored in neurons of the superior temporal cortex based on the location of candidate transcription factor motifs identified by two de novo motif discovery methods. Analyses were performed in parallel, both finding that PD risk variants significantly overlap with open chromatin regions harboring motifs of basic Helix-Loop-Helix (bHLH) transcription factors. Our findings show that cortical neurons are likely mediators of genetic risk for PD. The concentration of PD risk variants at sites of open chromatin targeted by members of the bHLH transcription factor family points to an involvement of these transcriptional networks in PD risk mechanisms.Victoria Berge-SeidlLasse PihlstrømMathias ToftNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Victoria Berge-Seidl Lasse Pihlstrøm Mathias Toft Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms
description	Abstract Genome-wide association studies (GWAS) have identified multiple genetic risk signals for Parkinson’s disease (PD), however translation into underlying biological mechanisms remains scarce. Genomic functional annotations of neurons provide new resources that may be integrated into analyses of GWAS findings. Altered transcription factor binding plays an important role in human diseases. Insight into transcriptional networks involved in PD risk mechanisms may thus improve our understanding of pathogenesis. We analysed overlap between genome-wide association signals in PD and open chromatin in neurons across multiple brain regions, finding a significant enrichment in the superior temporal cortex. The involvement of transcriptional networks was explored in neurons of the superior temporal cortex based on the location of candidate transcription factor motifs identified by two de novo motif discovery methods. Analyses were performed in parallel, both finding that PD risk variants significantly overlap with open chromatin regions harboring motifs of basic Helix-Loop-Helix (bHLH) transcription factors. Our findings show that cortical neurons are likely mediators of genetic risk for PD. The concentration of PD risk variants at sites of open chromatin targeted by members of the bHLH transcription factor family points to an involvement of these transcriptional networks in PD risk mechanisms.
format	article
author	Victoria Berge-Seidl Lasse Pihlstrøm Mathias Toft
author_facet	Victoria Berge-Seidl Lasse Pihlstrøm Mathias Toft
author_sort	Victoria Berge-Seidl
title	Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms
title_short	Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms
title_full	Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms
title_fullStr	Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms
title_full_unstemmed	Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms
title_sort	integrative analysis identifies bhlh transcription factors as contributors to parkinson’s disease risk mechanisms
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ae756f46afd749a8a90e72adbcf8655d
work_keys_str_mv	AT victoriabergeseidl integrativeanalysisidentifiesbhlhtranscriptionfactorsascontributorstoparkinsonsdiseaseriskmechanisms AT lassepihlstrøm integrativeanalysisidentifiesbhlhtranscriptionfactorsascontributorstoparkinsonsdiseaseriskmechanisms AT mathiastoft integrativeanalysisidentifiesbhlhtranscriptionfactorsascontributorstoparkinsonsdiseaseriskmechanisms
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Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms

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