The Endocytic Membrane Trafficking Pathway Plays a Major Role in the Risk of Parkinson’s Disease
| Autor: | Cristina Tejera-Parrado, Jean-christophe Corvol, Huw Morris, Rauan Kaiyrzhanov, Sebastian Schreglmann, Mie Rizig, Sara Bandrés Ciga, Francisco Javier Barrero Hernández, Patrick Lewis, Nicholas Wood, Claudia Schulte, John Quinn, Astrid Daniela Adarmes Gómez, Juan Carlos Martinez Castrillo, Berta María Pascual Sedano, Victoria Alvarez, Niccolò Emanuele Mencacci, Thomas Gasser, Ziv Gan-Or, Luis Bonet-Ponce, Adolfo Mínguez-Castellanos, Jose Bras, J. Raphael Gibbs, Monica Diez-Fairen, Viorica Chelban, Ruth Lovering, Jon Infante, Oriol Dols Icardo, Hirotaka Iwaki, Rita Guerreiro, John Hardy, Mario Ezquerra, Kin Ying Mok, Kerri J Kinghorn, Beatriz De la Casa-Fages, Peter Heutink, Manuel Menéndez González, Francisco Escamilla Sevilla, Sara Saez-Atienzar, Alexis Brice, Ignacio Alvarez, Pille Taba |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Linkage disequilibrium Parkinson's disease Endocytic cycle Neurodegenerative heritability genetic risk 0302 clinical medicine Risk Factors Missing heritability problem 2.1 Biological and endogenous factors Aetiology Genetics Parkinson Disease Single Nucleotide Endocytosis Neurology social and economic factors Clinical Sciences Quantitative Trait Loci Biology Quantitative trait locus Polymorphism Single Nucleotide 03 medical and health sciences 2.3 Psychological Decent Work and Economic Growth Mendelian randomization medicine Humans Genetic Predisposition to Disease Genetic Testing Polymorphism Genetic association Neurology & Neurosurgery Prevention Human Genome Neurosciences Human Movement and Sports Sciences Mendelian Randomization Analysis Heritability medicine.disease Brain Disorders 030104 developmental biology polygenic risk score Neurology (clinical) 030217 neurology & neurosurgery International Parkinson's Disease Genomics Consortium Genome-Wide Association Study |
| Zdroj: | Movement Movement disorders : official journal of the Movement Disorder Society, vol 34, iss 4 |
| Popis: | Background PD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed. Objectives To comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD. Methods Linkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci. Results The heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk. Conclusions We provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions. © 2019 International Parkinson and Movement Disorder Society. |
| Databáze: | OpenAIRE |
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