Characterizing a complex CT-rich haplotype in intron 4 of SNCA using large-scale targeted amplicon long-read sequencing

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dc.citation.articleNumber136en_US
dc.citation.journalTitlenpj Parkinson's Diseaseen_US
dc.citation.volumeNumber10en_US
dc.contributor.authorAlvarez Jerez, Pilaren_US
dc.contributor.authorDaida, Kensukeen_US
dc.contributor.authorGrenn, Francis P.en_US
dc.contributor.authorMalik, Lakshen_US
dc.contributor.authorMiano-Burkhardt, Abigailen_US
dc.contributor.authorMakarious, Mary B.en_US
dc.contributor.authorDing, Jinhuien_US
dc.contributor.authorGibbs, J. Raphaelen_US
dc.contributor.authorMoore, Annien_US
dc.contributor.authorReed, Xylenaen_US
dc.contributor.authorNalls, Mike A.en_US
dc.contributor.authorShah, Syeden_US
dc.contributor.authorMahmoud, Medhaten_US
dc.contributor.authorSedlazeck, Fritz J.en_US
dc.contributor.authorDolzhenko, Egoren_US
dc.contributor.authorPark, Morganen_US
dc.contributor.authorIwaki, Hirotakaen_US
dc.contributor.authorCasey, Bradforden_US
dc.contributor.authorRyten, Minaen_US
dc.contributor.authorBlauwendraat, Cornelisen_US
dc.contributor.authorSingleton, Andrew B.en_US
dc.contributor.authorBillingsley, Kimberley J.en_US
dc.date.accessioned2024-08-09T16:25:26Zen_US
dc.date.available2024-08-09T16:25:26Zen_US
dc.date.issued2024en_US
dc.description.abstractParkinson’s disease (PD) is a common neurodegenerative disorder with a significant risk proportion driven by genetics. While much progress has been made, most of the heritability remains unknown. This is in-part because previous genetic studies have focused on the contribution of single nucleotide variants. More complex forms of variation, such as structural variants and tandem repeats, are already associated with several synucleinopathies. However, because more sophisticated sequencing methods are usually required to detect these regions, little is understood regarding their contribution to PD. One example is a polymorphic CT-rich region in intron 4 of the SNCA gene. This haplotype has been suggested to be associated with risk of Lewy Body (LB) pathology in Alzheimer’s Disease and SNCA gene expression, but is yet to be investigated in PD. Here, we attempt to resolve this CT-rich haplotype and investigate its role in PD. We performed targeted PacBio HiFi sequencing of the region in 1375 PD cases and 959 controls. We replicate the previously reported associations and a novel association between two PD risk SNVs (rs356182 and rs5019538) and haplotype 4, the largest haplotype. Through quantitative trait locus analyzes we identify a significant haplotype 4 association with alternative CAGE transcriptional start site usage, not leading to significant differential SNCA gene expression in post-mortem frontal cortex brain tissue. Therefore, disease association in this locus might not be biologically driven by this CT-rich repeat region. Our data demonstrates the complexity of this SNCA region and highlights that further follow up functional studies are warranted.en_US
dc.identifier.citationAlvarez Jerez, P., Daida, K., Grenn, F. P., Malik, L., Miano-Burkhardt, A., Makarious, M. B., Ding, J., Gibbs, J. R., Moore, A., Reed, X., Nalls, M. A., Shah, S., Mahmoud, M., Sedlazeck, F. J., Dolzhenko, E., Park, M., Iwaki, H., Casey, B., Ryten, M., … Billingsley, K. J. (2024). Characterizing a complex CT-rich haplotype in intron 4 of SNCA using large-scale targeted amplicon long-read sequencing. Npj Parkinson’s Disease, 10(1), 1–8. https://doi.org/10.1038/s41531-024-00749-4en_US
dc.identifier.digitals41531-024-00749-4en_US
dc.identifier.doihttps://doi.org/10.1038/s41531-024-00749-4en_US
dc.identifier.urihttps://hdl.handle.net/1911/117644en_US
dc.language.isoengen_US
dc.publisherSpringer Natureen_US
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license.  Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleCharacterizing a complex CT-rich haplotype in intron 4 of SNCA using large-scale targeted amplicon long-read sequencingen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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