Genome‐Wide Analysis of Structural Variants in Parkinson Disease

Billingsley, Kimberley; Ding, Jinhui; Jerez, Pilar Alvarez; Illarionova, Anastasia; Levine, Kristin; Grenn, Francis P.; Makarious, Mary B.; Moore, Anni; Vitale, Daniel; Reed, Xylena; Hernandez, Dena G.; Torkamani, Ali; Ryten, Mina; Chia, Ruth; Scholz, Sonja W.; Traynor, Bryan J.; Dalgard, Clifton L.; Ehrlich, Debra; Tanaka, Toshiko; Ferrucci, Luigi; Beach, Thomas G.; Serrano, Geidy E.; Quinn, John P.; Bubb, Vivien J.; Collins, Ryan L.; Zhao, Xuefang; Walker, Mark; Pierce‐Hoffman, Emma; Brand, Harrison; Talkowski, Michael E.; Casey, Bradford; Cookson, Mark; Markham, Androo J.; Nalls, Mike A.; Mahmoud, Medhat; Sedlazeck, Fritz J.; Blauwendraat, Cornelis; Gibbs, J. Raphael; Singleton, Andrew B.

doi:10.1002/ana.26608

Cited by 19 publications

(18 citation statements)

References 51 publications

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“…Long-read sequencing revealed a large inversion expanding 7.4 M bp with 5 0 breakpoint in intron 11 of PRKN, removing exon 12 from PRKN transcripts. In agreement with recent studies, 20 our study highlights that long-read sequencing can be used to identify new SVs in the PD population, especially in PRKN-PD.…”

Section: Discussionsupporting

confidence: 92%

“…Not only do longer reads (10 kb+) improve de novo assembly and mapping, but they are better able to detect SVs because they can span repetitive or other complex regions of the genome. For identifying SVs in PD specifically, a recent study that compared matched long and short sequencing read data from PD cases highlighted that most SVs in the human genome are likely undetectable with short‐read data alone (~84%) 20 . Long‐read sequencing is a powerful tool for identifying potential causal variants that were previously undetectable using other sequencing technologies.…”

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confidence: 99%

“…For identifying SVs in PD specifically, a recent study that compared matched long and short sequencing read data from PD cases highlighted that most SVs in the human genome are likely undetectable with short-read data alone (84%). 20 Longread sequencing is a powerful tool for identifying potential causal variants that were previously undetectable using other sequencing technologies.…”

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confidence: 99%

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Long‐Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease

Daida,

Funayama,

Billingsley

et al. 2023

Movement Disorders

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BackgroundParkin RBR E3 ubiquitin‐protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants.ObjectivesTo identify complex structural variants in PRKN using long‐read sequencing.MethodsWe investigated the genetic cause of monozygotic twins presenting with a young onset dystonia‐parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long‐read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole‐genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP‐PD) and United Kingdom (UK)‐Biobank datasets.ResultsMultiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long‐read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK‐Biobank and 4941 participants of the AMP‐PD datasets. Nine inversions in the UK‐Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression.ConclusionsThis is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long‐read sequencing for structural variant analysis in unresolved young‐onset PD cases. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

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confidence: 99%

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Long‐Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease

Daida,

Funayama,

Billingsley

et al. 2023

Movement Disorders

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“…However, short-read sequencing and techniques such as MPRA cannot typically capture these forms of variation, and thus it has been hard to depict the contribution of such variants to disease risk 61 . The fast-growing application of long-read sequencing, and inference using short-read sequencing, is beginning to provide insight into the impacts of other forms of variation 62 , 63 . Moving forward, it will be important to consider the functional implications of identified SVs associated with PD, and also potential interaction and/or epistatic effects occurring between SVs and SNPs 64 .…”

Section: Discussionmentioning

confidence: 99%

Identification of 27 allele-specific regulatory variants in Parkinson’s disease using a massively parallel reporter assay

Farrow,

Gokuladhas,

Schierding

et al. 2024

npj Parkinsons Dis.

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Genome wide association studies (GWAS) have identified a number of genomic loci that are associated with Parkinson’s disease (PD) risk. However, the majority of these variants lie in non-coding regions, and thus the mechanisms by which they influence disease development, and/or potential subtypes, remain largely elusive. To address this, we used a massively parallel reporter assay (MPRA) to screen the regulatory function of 5254 variants that have a known or putative connection to PD. We identified 138 loci with enhancer activity, of which 27 exhibited allele-specific regulatory activity in HEK293 cells. The identified regulatory variant(s) typically did not match the original tag variant within the PD associated locus, supporting the need for deeper exploration of these loci. The existence of allele specific transcriptional impacts within HEK293 cells, confirms that at least a subset of the PD associated regions mark functional gene regulatory elements. Future functional studies that confirm the putative targets of the empirically verified regulatory variants will be crucial for gaining a greater understanding of how gene regulatory network(s) modulate PD risk.

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“…A more detailed and targeted analysis is required to understand the role of transposable elements within PD and other neurodegenerative diseases. Billingsley et al performed a genome-wide structural variant analysis by testing over 3,154 structural variant loci in PD which increased the understanding of genetic variations at PD risk loci 12 .…”

Section: Introductionmentioning

confidence: 99%

Reference LINE-1 insertion polymorphisms correlate with Parkinson’s disease progression and differential transcript expression in the PPMI cohort

Fröhlich,

Pfaff,

Bubb

et al. 2023

Sci Rep

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Long interspersed nuclear element-1 (LINE-1/L1) retrotransposons make up 17% of the human genome. They represent one class of transposable elements with the capacity to both mobilize autonomously and in trans via the mobilization of other elements, primarily Alu and SVA elements. Reference LINE-1 elements are, by definition, found in the reference genome, however, due to the polymorphic nature of these elements, variation for presence or absence is present within the population. We used a combination of clinical and transcriptomic data from the Parkinson’s Progression Markers Initiative (PPMI) and applied matrix expression quantitative trait loci analysis and linear mixed-effects models involving 114 clinical, biochemical and imaging data from the PPMI cohort to elucidate the role of reference LINE-1 insertion polymorphism on both gene expression genome-wide and progression of Parkinson’s disease (PD). We demonstrate that most LINE-1 insertion polymorphisms are capable of regulating gene expression, preferentially in trans, including previously identified PD risk loci. In addition, we show that 70 LINE-1 elements were associated with longitudinal changes of at least one PD progression marker, including ipsilateral count density ratio and UPDRS scores which are indicators of degeneration and severity. In conclusion, this study highlights the effect of the polymorphic nature of LINE-1 retrotransposons on gene regulation and progression of PD which underlines the importance of analyzing transposable elements within complex diseases.

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Genome‐Wide Analysis of Structural Variants in Parkinson Disease

Cited by 19 publications

References 51 publications

Long‐Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease

Long‐Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease

Identification of 27 allele-specific regulatory variants in Parkinson’s disease using a massively parallel reporter assay

Reference LINE-1 insertion polymorphisms correlate with Parkinson’s disease progression and differential transcript expression in the PPMI cohort

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