A comprehensive analysis of <i>SNCA</i>‐related genetic risk in sporadic parkinson disease

Pihlstrøm, Lasse; Blauwendraat, Cornelis; Cappelletti, Chiara; Berge-Seidl, Victoria; Langmyhr, Margrete; Henriksen, Sandra Pilar; Berg, Wilma D. J. van de; Gibbs, J. Raphael; Cookson, Mark; Singleton, Andrew B.; Nalls, Mike A.; Toft, Mathias

doi:10.1002/ana.25274

Cited by 54 publications

(88 citation statements)

References 54 publications

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“…The top signal is rs356181 (see Fig , OR = 1.62, 95% CI = 1.13–1.41, p = 9.9E‐05), which is in LD with the top PD GWAS hit, rs356182 ( R 2 = 0.63, D′ = 0.99, see Fig 2A), suggesting that these associations may be driven by the same variant. After conditioning on the top signal, a second 3′ signal was identified at rs2870006 (OR = 0.84, 95% CI = 0.75–0.95, p = 0.0034), also in LD with previously found 3′ signal at rs2870004 ( R 2 = 0.21, D′ = 0.99), representing the first independent replication of this association. These SNPs were not in LD with the iRBD 2 top signals (see Table ) and at a separate location from the top iRBD signals (see Fig ), suggesting that they are independent.…”

Section: Resultssupporting

confidence: 70%

“…Unlike the 5′ variants, these are independent signals (PD top 3′, PD novel 3′, and RBD 3′; see Fig 2A). The recently reported novel 3′ risk locus for PD (PD novel 3′, rs2870004) was significantly associated with pRBD (meta‐analysis OR = 0.76, 95% CI = 0.62–0.94, p = 0.009) but showed no differences in allele frequencies of DLB + pRBD versus DLB − pRBD, suggesting that this may be a PD‐specific signal. Results are inconclusive for the PD top 3′ GWAS variant rs356182, showing discrepant distributions of allele frequencies across these cohorts (see Fig 3C).…”

Section: Resultsmentioning

confidence: 99%

“…The number of independent tests for multiple testing correction was determined according to pruned number of SNCA SNPs with MAF > 0.05 by R 2 > 0.5 (n = 191) to avoid an overly stringent significance threshold by correcting separately for SNPs that are in high LD and represent the same haplotype. This method set the Bonferroni‐corrected significance threshold at p < 2.6E‐04, which is in line with previously established thresholds in the same SNCA region . Logistic regression was performed in a stepwise forward method as previously described .…”

Section: Methodsmentioning

confidence: 99%

“…Data were converted to PLINK format and merged using only SNPs genotyped on both platforms (n = ~160,000). Oslo and PPMI PD samples were genotyped as previously described …”

Section: Methodsmentioning

confidence: 99%

“…Oslo and PPMI PD samples were genotyped as previously described. 23,36 To exclude low-quality SNPs and samples, quality control (QC) was performed on the variant level (SNPs excluded if genotype quality <95%, missingness >5%, divergent call rates between cases and controls p < 1E-04, or departure from the Hardy-Weinberg equilibrium p < 1E-04) and on the sample level (samples excluded if genotype data showed missingness in >5%, abnormal heterozygosity, conflicting sex assignment, cryptic relatedness at p > 0.125, or non-European ancestry). This QC was separately performed on each cohort and then performed again when data were merged for analysis.…”

Section: Methodsmentioning

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: Resultssupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Data were converted to PLINK format and merged using only SNPs genotyped on both platforms (n = ~160,000). Oslo and PPMI PD samples were genotyped as previously described …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

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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Characterizing the Genetic Architecture of Parkinson's Disease in Latinos

Loesch

Horimoto

Heilbron

et al. 2021

Annals of Neurology

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Objective This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European‐ancestry subjects, and to increase the diversity in PD genome‐wide association (GWAS) data. Methods We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p‐value <1 × 10−5 were tested in a replication cohort of 1,234 self‐reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. Results One locus, SNCA, achieved genome‐wide significance (p‐value <5 × 10−8); rs356182 achieved genome‐wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35–1.86, p‐value 2.48 × 10−8; 23andMe, G allele: 1.26 OR, 95% CI 1.16–1.37, p‐value 4.55 × 10−8). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single‐ancestry test (p‐value <5 × 10−5). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single‐ancestry test (p‐value <5 × 10−5). Interpretation This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353–365

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Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms

et al. 2019

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Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome‐wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives To identify the genetic determinants of PD age at onset. Methods Using genetic data of 28,568 PD cases, we performed a genome‐wide association study based on PD age at onset. Results We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome‐wide significant association signals, one at SNCA and the other a protein‐coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni‐corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α‐synuclein aggregation pathways. Remarkably, other well‐established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions Overall, we have performed the largest age at onset of PD genome‐wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease‐linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society

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A comprehensive analysis of SNCA‐related genetic risk in sporadic parkinson disease

Cited by 54 publications

References 54 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

Characterizing the Genetic Architecture of Parkinson's Disease in Latinos

Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms

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