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

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dc.creatorAlvarez Jerez, Pilar
dc.creatorDaida, Kensuke
dc.creatorGrenn, Francis P
dc.creatorMalik, Laksh
dc.creatorMiano-Burkhardt, Abigail
dc.creatorMakarious, Mary B
dc.creatorDing, Jinhui
dc.creatorGibbs, J Raphael
dc.creatorMoore, Anni
dc.creatorReed, Xylena
dc.creatorNalls, Mike A
dc.creatorShah, Syed
dc.creatorMahmoud, Medhat
dc.creatorSedlazeck, Fritz J
dc.creatorDolzhenko, Egor
dc.creatorPark, Morgan
dc.creatorIwaki, Hirotaka
dc.creatorCasey, Bradford
dc.creatorRyten, Mina
dc.creatorBlauwendraat, Cornelis
dc.creatorSingleton, Andrew B
dc.creatorBillingsley, Kimberley J
dc.date2024-08-01T12:30:05Z
dc.date2024-07-26
dc.date2024-01-29
dc.date2024-08-01T12:30:05Z
dc.date.accessioned2026-08-03T04:05:19Z
dc.descriptionParkinson'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.
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dc.formatapplication/pdf
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dc.identifier2373-8057
dc.identifiers41531-024-00749-4
dc.identifier749
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/371971
dc.identifier2373-8057
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/184785
dc.languageen
dc.languageeng
dc.publisherSpringer Nature
dc.publisherhttps://doi.org/10.1038/s41531-024-00749-4
dc.rightsAttribution 4.0 International
dc.rightshttp://creativecommons.org/licenses/by/4.0/
dc.subject32 Biomedical and Clinical Sciences
dc.subject5202 Biological Psychology
dc.subject5204 Cognitive and Computational Psychology
dc.subject3209 Neurosciences
dc.subject52 Psychology
dc.subjectDementia
dc.subjectBiotechnology
dc.subjectHuman Genome
dc.subjectParkinson's Disease
dc.subjectNeurodegenerative
dc.subjectAging
dc.subjectAcquired Cognitive Impairment
dc.subjectAlzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
dc.subjectNeurosciences
dc.subjectBrain Disorders
dc.subjectAlzheimer's Disease Related Dementias (ADRD)
dc.subjectLewy Body Dementia
dc.subjectGenetics
dc.subject2.1 Biological and endogenous factors
dc.subjectNeurological
dc.titleCharacterizing a complex CT-rich haplotype in intron 4 of SNCA using large-scale targeted amplicon long-read sequencing.
dc.typeArticle

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