Analysis of common and rare <i>VPS13C</i> variants in late onset Parkinson disease

Rudakou, Uladzislau; Ruskey, Jennifer A.; Krohn, Lynne; Laurent, Sandra B.; Spiegelman, Dan; Greenbaum, Lior; Yahalom, Gilad; Désautels, Alex; Montplaisir, Jacques; Fahn, Stanley; Waters, Cheryl; Levy, Oren; Kehoe, Caitlin M.; Narayan, Sushma; Dauvilliers, Yves; Dupré, Nicolas; Hassin‐Baer, Sharon; Alcalay, Roy N.; Rouleau, Guy A.; Fon, Edward A.; Gan‐Or, Ziv

doi:10.1101/705533

Cited by 11 publications

(16 citation statements)

References 22 publications

(27 reference statements)

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“…The full protocol is available online at https://github.com/gan-orlab/MIP_protocol. Alignment (GRCh37/hg19), quality control (QC), and variant calls were done using the Burrows‐Wheeler Aligner (BWA), 41 Genome Analysis Toolkit (GATK v3.8), 42 and ANNOVAR 43 as previously described 44 . Only rare variants (minor allele frequency [MAF] <0.01) according to the public database Genome Aggregation Database (GnomAD) 45 with a minimum coverage of 30× were included in the analysis.…”

Section: Methodsmentioning

confidence: 99%

Analysis of Heterozygous PRKN Variants and Copy‐Number Variations in Parkinson's Disease

Rudakou

Krohn

et al. 2020

Movement Disorders

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Background Biallelic PRKN mutation carriers with Parkinson's disease (PD) typically have an earlier disease onset, slow disease progression, and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial. Objectives Our aim was to examine the association between heterozygous PRKN variants, including single‐nucleotide variants and copy‐number variations (CNVs), and PD. Methods We fully sequenced PRKN in 2809 PD patients and 3629 healthy controls, including 1965 late‐onset (63.97 ± 7.79 years, 63% men) and 553 early‐onset PD patients (43.33 ± 6.59 years, 68% men). PRKN was sequenced using targeted next‐generation sequencing with molecular inversion probes. CNVs were identified using a combination of multiplex ligation‐dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single‐nucleotide variants and CNVs in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models. Results We did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely‐pathogenic heterozygous single‐nucleotide variants and CNVs were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate‐corrected P = 0.55). No associations with age at onset and in stratified analyses were found. Conclusions Heterozygous single‐nucleotide variants and CNVs in PRKN are not associated with PD. Molecular inversion probes allow for rapid and cost‐effective detection of all types of PRKN variants, which may be useful for pretrial screening and for clinical and basic science studies targeting specifically PRKN patients. © 2020 International Parkinson and Movement Disorder Society

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Section: Methodsmentioning

confidence: 99%

Analysis of Heterozygous PRKN Variants and Copy‐Number Variations in Parkinson's Disease

Rudakou

Krohn

et al. 2020

Movement Disorders

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“…VPS13C is likely to contain deleterious, protective and null variants. Recently, a VPS13C haplotype including the common (MAF > 1%) variants p.R153H-p.I398I-p.I1132V-p.Q2376Q was associated with a reduced risk for PD (p = 0.0052, odds ratio = 0.48, 95% con dence interval = 0.28-0.82) [63]. The same study, which included 1.567 late-onset PD patients, did not observe a statistically signi cant burden of rare (MAF ≤ 1%) VPS13C variants in PD, neither bi-allelic, non-synonymous coding and splice site variants in VPS13C in patients [63].…”

Section: Discussionmentioning

confidence: 98%

“…Recently, a VPS13C haplotype including the common (MAF > 1%) variants p.R153H-p.I398I-p.I1132V-p.Q2376Q was associated with a reduced risk for PD (p = 0.0052, odds ratio = 0.48, 95% con dence interval = 0.28-0.82) [63]. The same study, which included 1.567 late-onset PD patients, did not observe a statistically signi cant burden of rare (MAF ≤ 1%) VPS13C variants in PD, neither bi-allelic, non-synonymous coding and splice site variants in VPS13C in patients [63]. However, this study only included compound heterozygous variants with a MAF < 0.1% in late-onset patients, while we included variants with a MAF < 1% in both early-and late-onset patients.…”

Section: Discussionmentioning

confidence: 98%

Homozygous and compound heterozygous rare variants in VPS13C contribute to Lewy body diseases

Smolders

Philtjens

Crosiers

et al. 2020

Preprint

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Background Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and etiologically overlapping disorders. They are included in the Lewy body disease (LBD) continuum characterized by α-synuclein-positive Lewy body pathology in neurons. Homozygous PTC mutations in Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset PD. Methods Whole genome sequencing of two affected siblings and healthy parents of family A with onset age below 50 years and DLB pathology confirmed at autopsy. Targeted resequencing of the VPS13C coding region in 844 LBD patients and 664 control individuals. Phasing cis-trans location of the compound heterozygous VPS13C variants. Analysis of VPS13C protein expression in lymphoblast cells and brain lysates. Immunohistochemistry and live cell labeling in HeLa and SH-SY5Y cells overexpressing wild type or mutant VPS13C. Results In the two affected siblings of family A, we identified compound heterozygous rare variants located in trans in VPS13C Rare VPS13C variants (MAF ≤ 1%), are significantly associated (p = 0.0233) in the LBD patient cohort using optimized sequence kernel association test (SKAT-O). We identified 11 carriers of compound heterozygous variants and 1 carrier of homozygous variants in VPS13C. Trans location of the variants in compound heterozygous carriers was confirmed in 4 and cis location in 3 patients. The frequency of patient carriers with bi-allelic variants mimicking recessive inheritance is 1.07% (9/844). In post-mortem brain tissue of two unrelated DLB carriers of compound trans heterozygous variants, we observed a reduction of VPS13C protein expression. Overexpressing of wild type or mutant VPS13C, in HeLa and SH-SY5Y cells, demonstrated that the mutations abolish the endosomal/lysosomal localization of VPS13C. Conclusions Our data indicate that rare alleles are associated with LBD, and when present bi-allelic in patients, these combinations have variable effects on expression and functioning of VPS13C. Apart from the recessive PTC mutations, some combinations of rare missense mutations might mimic recessive inheritance and explain part of the sporadic LBD patients. We propose that homozygous or compound heterozygous rare missense variants in VPS13C reducing VPS13C protein expression can contribute to risk of LBD.

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“…For example, rare variants in GWAS loci genes including SNCA, GBA,LRRK2,VPS13C and GCH1 may cause Mendelian parkinsonism or strongly increase the risk of Parkinson's disease. (Polymeropoulos et al, 1997;Sidransky et al, 2009;Ran et al, 2016;Emelyanov et al, 2018;Amaral et al, 2019;Paisan-Ruiz et al, 2004;Khan et al, 2005;Lesage et al, 2016;Jansen et al, 2017;Darvish et al, 2018;Schormair et al, 2018;Rudakou et al, 2020;Mencacci et al, 2014;Guella et al, 2015;Lewthwaite et al, 2015;Xu et al, 2017;Yoshino et al, 2018;Rudakou et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Targeted sequencing of Parkinson’s disease loci genes highlights SYT11, FGF20 and other associations

Rudakou

Krohn

et al. 2020

Brain

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Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson’s disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson’s disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson’s disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3′ UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10−5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5′ UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson’s disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson’s disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson’s disease (odds ratio 0.73, 95% confidence interval 0.60–0.89, P = 1.161 × 10−3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson’s disease-related genes.

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Analysis of common and rare VPS13C variants in late onset Parkinson disease

Cited by 11 publications

References 22 publications

Analysis of Heterozygous PRKN Variants and Copy‐Number Variations in Parkinson's Disease

Analysis of Heterozygous PRKN Variants and Copy‐Number Variations in Parkinson's Disease

Homozygous and compound heterozygous rare variants in VPS13C contribute to Lewy body diseases

Targeted sequencing of Parkinson’s disease loci genes highlights SYT11, FGF20 and other associations

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