The landscape of <i>SNCA</i> transcripts across synucleinopathies: New insights from long reads sequencing analysis

Tseng, Elizabeth; Rowell, William J; Omolara-Chinue, Glenn; Hon, Ting; Barrera, Julio; Kujawa, Steve; Chiba‐Falek, Ornit

doi:10.1101/524827

Cited by 4 publications

(4 citation statements)

References 23 publications

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“…Finally, the RBD 5 0 variant rs10005233 has been linked to novel alternative 3 0 -end SNCA isoforms (PB.1016.383, PB.1016.384), associated with a truncated open reading frame prediction. 50 These findings suggest potential functional effects of some of these variants, but they need to be further replicated and studied.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, a variant in the 3′ end of the intron‐4 enhancer region rs356168‐A has been associated with increased levels of α‐synuclein in human induced pluripotent stem cells and is in LD with the top signal for PD rs356182‐A ( R 2 = 0.50, D′ = 0.91). Finally, the RBD 5′ variant rs10005233 has been linked to novel alternative 3′‐end SNCA isoforms (PB.1016.383, PB.1016.384), associated with a truncated open reading frame prediction . These findings suggest potential functional effects of some of these variants, but they need to be further replicated and studied.…”

Section: Discussionmentioning

confidence: 99%

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Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Krohn

Heilbron

et al. 2020

Annals of Neurology

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Objective Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in‐depth analysis of the SNCA locus to identify RBD‐specific risk variants. Methods Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta‐analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results A 5′‐region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E‐08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD‐specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E‐04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD‐specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E‐06). The known top PD‐associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Krohn

Heilbron

et al. 2020

Annals of Neurology

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show abstract

“…Finally, the top RBD variant rs10005233 has been linked to novel alternative 3′-end SNCA isoforms (PB.1016.383, PB.1016.384), associated with a truncated open reading frame prediction. 48 These findings suggest potential functional effects of some of these variants, but they need to be further replicated and studied.…”

Section: Discussionmentioning

confidence: 99%

Fine-mapping of SNCA in REM sleep behavior disorder and overt synucleinopathies

Krohn

Heilbron³

et al. 2019

Preprint

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Objective: REM-sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods:Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n=1,076), Parkinson's disease (PD, n=1,013), and dementia with Lewy bodies (DLB, n=415), and in control subjects (n=6,155). A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (cases n=1,782, controls n=131,250). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.Results: A 5'-region SNCA variant (rs10005233) was associated with iRBD (OR=1.43, p=1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR=1.32, p=4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR=5.74, p=2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD.Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies, and may suggest a cognitive component to this region.Fine-mapping of SNCA in RBD

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“…This manuscript has been released as a pre-print at BioRxiv (Tseng et al, 2019). https://www.biorxiv.org/content/10.1101/524827v1.…”

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confidence: 99%

The Landscape of SNCA Transcripts Across Synucleinopathies: New Insights From Long Reads Sequencing Analysis

et al. 2019

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Dysregulation of alpha-synuclein expression has been implicated in the pathogenesis of synucleinopathies, in particular Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Previous studies have shown that the alternatively spliced isoforms of the SNCA gene are differentially expressed in different parts of the brain for PD and DLB patients. Similarly, SNCA isoforms with skipped exons can have a functional impact on the protein domains. The large intronic region of the SNCA gene was also shown to harbor structural variants that affect transcriptional levels. Here, we apply the first study of using long read sequencing with targeted capture of both the gDNA and cDNA of the SNCA gene in brain tissues of PD, DLB, and control samples using the PacBio Sequel system. The targeted full-length cDNA (Iso-Seq) data confirmed complex usage of known alternative start sites and variable 3′ UTR lengths, as well as novel 5′ starts and 3′ ends not previously described. The targeted gDNA data allowed phasing of up to 81% of the ~114 kb SNCA region, with the longest phased block exceeding 54 kb. We demonstrate that long gDNA and cDNA reads have the potential to reveal long-range information not previously accessible using traditional sequencing methods. This approach has a potential impact in studying disease risk genes such as SNCA, providing new insights into the genetic etiologies, including perturbations to the landscape the gene transcripts, of human complex diseases such as synucleinopathies.

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The landscape of SNCA transcripts across synucleinopathies: New insights from long reads sequencing analysis

Cited by 4 publications

References 23 publications

Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Fine-mapping of SNCA in REM sleep behavior disorder and overt synucleinopathies

The Landscape of SNCA Transcripts Across Synucleinopathies: New Insights From Long Reads Sequencing Analysis

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