Dataset Information

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

ABSTRACT: 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 ?-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.

SUBMITTER: Blauwendraat C

PROVIDER: S-EPMC6579628 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Blauwendraat Cornelis C Heilbron Karl K Vallerga Costanza L CL Bandres-Ciga Sara S von Coelln Rainer R Pihlstrøm Lasse L Simón-Sánchez Javier J Schulte Claudia C Sharma Manu M Krohn Lynne L Siitonen Ari A Iwaki Hirotaka H Leonard Hampton H Noyce Alastair J AJ Tan Manuela M Gibbs J Raphael JR Hernandez Dena G DG Scholz Sonja W SW Jankovic Joseph J Shulman Lisa M LM Lesage Suzanne S Corvol Jean-Christophe JC Brice Alexis A van Hilten Jacobus J JJ Marinus Johan J Eerola-Rautio Johanna J Tienari Pentti P Majamaa Kari K Toft Mathias M Grosset Donald G DG Gasser Thomas T Heutink Peter P Shulman Joshua M JM Wood Nicolas N Hardy John J Morris Huw R HR Hinds David A DA Gratten Jacob J Visscher Peter M PM Gan-Or Ziv Z Nalls Mike A MA Singleton Andrew B AB

Movement disorders : official journal of the Movement Disorder Society 20190407 6

<h4>Background</h4>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.<h4>Objectives</h4>To identify the genetic determinants of PD age at onset.<h4>Methods</h4>Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset.<h4>Results</h4 ...[more]

PMID: 30957308

Similar Datasets

Project description:Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of α-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood α-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of α-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets