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

Annals of Neurology
Lasse PihlstrømMathias Toft

Abstract

The goal of this study was to refine our understanding of disease risk attributable to common genetic variation in SNCA, a major locus in Parkinson disease, with potential implications for clinical trials targeting α-synuclein. We aimed to dissect the multiple independent association signals, stratify individuals by SNCA-specific risk profiles, and explore expression quantitative trait loci. We analyzed participant-level data from 12,503 patients and 12,502 controls, optimizing a risk model and assessing SNCA-specific risk scores and haplotypes as predictors of individual risk. We also explored hypotheses about functional mechanisms and correlated risk variants to gene expression in human brain and protein levels in cerebrospinal fluid. We report and replicate a novel, third independent association signal at genome-wide significance level downstream of SNCA (rs2870004, p = 3.0*10-8 , odds ratio [OR] = 0.88, 95% confidence interval [CI] = 0.84-0.92). SNCA risk score stratification showed a 2-fold difference in disease susceptibility between top and bottom quintiles (OR = 1.99, 95% CI = 1.78-2.23). Contrary to previous reports, we provide evidence supporting top variant rs356182 as functional in itself and associated with a speci...Continue Reading

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Apr 9, 2019·Movement Disorders : Official Journal of the Movement Disorder Society·Cornelis BlauwendraatUNKNOWN International Parkinson's Disease Genomics Consortium (IPDGC)
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Apr 22, 2019·Acta Neuropathologica·Javier Alegre-AbarrateguiChristos Proukakis
Dec 12, 2020·Neurobiology of Disease·Cornelis BlauwendraatAndrew B Singleton
May 18, 2021·Frontiers in Pharmacology·Alfonsina TirozziTeresa Esposito
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Jul 7, 2021·Annals of Neurology·Douglas P LoeschUNKNOWN Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD)
Jul 28, 2021·NPJ Parkinson's Disease·Luis M A OliveiraTiago F Outeiro
Jul 3, 2021·NPJ Parkinson's Disease·Camilla Christina PedersenJodi Maple-Grødem

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