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A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

ABSTRACT: BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

SUBMITTER: Sharma M

PROVIDER: S-EPMC3488700 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

Sharma Manu M Ioannidis John P A JP Aasly Jan O JO Annesi Grazia G Brice Alexis A Bertram Lars L Bozi Maria M Barcikowska Maria M Crosiers David D Clarke Carl E CE Facheris Maurizio F MF Farrer Matthew M Garraux Gaetan G Gispert Suzana S Auburger Georg G Vilariño-Güell Carles C Hadjigeorgiou Georgios M GM Hicks Andrew A AA Hattori Nobutaka N Jeon Beom S BS Jamrozik Zygmunt Z Krygowska-Wajs Anna A Lesage Suzanne S Lill Christina M CM Lin Juei-Jueng JJ Lynch Timothy T Lichtner Peter P Lang Anthony E AE Libioulle Cecile C Murata Miho M Mok Vincent V Jasinska-Myga Barbara B Mellick George D GD Morrison Karen E KE Meitnger Thomas T Zimprich Alexander A Opala Grzegorz G Pramstaller Peter P PP Pichler Irene I Park Sung Sup SS Quattrone Aldo A Rogaeva Ekaterina E Ross Owen A OA Stefanis Leonidas L Stockton Joanne D JD Satake Wataru W Silburn Peter A PA Strom Tim M TM Theuns Jessie J Tan Eng-King EK Toda Tatsushi T Tomiyama Hiroyuki H Uitti Ryan J RJ Van Broeckhoven Christine C Wirdefeldt Karin K Wszolek Zbigniew Z Xiromerisiou Georgia G Yomono Harumi S HS Yueh Kuo-Chu KC Zhao Yi Y Gasser Thomas T Maraganore Demetrius D Krüger Rejko R

Journal of medical genetics 20121101 11

<h4>Background</h4>Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.<h4>Methods and results</h4>We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p. ...[more]

PMID: 23125461

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Project description:ObjectiveThe aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available.MethodsWe calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses.ResultsA higher polygenic resilience score was associated with a lower risk for PD (β = -0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.InterpretationThe present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270-278.

Dataset Information

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

Publications

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

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