The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease
Open accessAbstract
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.
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At least three candidate genes within novel loci are involved in lysosomal storage disorders (GUSB, GRN, and NEU1).
“At least three candidate genes within novel loci are involved in lysosomal storage disorders (GUSB, GRN, and NEU1), a pathway of keen interest in PD (37).”
From Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies (2019) · cites this paper as [37]
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Endosomal trafficking leads the way in Parkinson's disease
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- Authors
- Bandres‐Ciga, S., Saez‐Atienzar, S., Bonet‐Ponce, L., Billingsley, K., Vitale, D., Blauwendraat, C., Gibbs, J. R., Pihlstrøm, L., Gan‐Or, Z., The International Parkinson's Disease Genomics Consortium (IPDGC), Cookson, M. R., Nalls, M. A., & Singleton, A. B.
- Affiliations
- Molecular Genetics Section, Laboratory of Neurogenetics National Institute on Aging, National Institutes of Health Bethesda Maryland USA
- Transgenics Section, Laboratory of Neurogenetics National Institute on Aging, National Institutes of Health Bethesda Maryland USA
- National Institutes of Health (US)
- Oslo University Hospital (NO)
- Montreal Neurological Institute and Hospital (CA)
- Corresponding author
- Singleton, Andrew B.
- ORCID
- Venue
- Movement Disorders
- Publisher
- Wiley
- Published
- 2019-01-24
- Volume
- 34
- Issue
- 4
- Pages
- 460-468
- ISSN
- 0885-3185 (ISSN-L)
- 1531-8257
- PMC
- PMC6467788
- OpenAlex
- W2913803346
- Cited by
- 90
- References
- 54
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 7 · 2023: 6 · 2022: 24 · 2021: 19 · 2020: 12 · 2019: 7
- FWCI
- 10.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Movement Disorders (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- Murdoch University Research Portal (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health (1ZIA‐NS003154, Z01‐AG000949‐02, Z01‐ES101986)
- U.S. Department of Defense (W81XWH‐09‐2‐0128)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, genetic risk factors, heritability, polygenic risk score, missing heritability, Mendelian randomization, expression quantitative trait loci, DNA methylation quantitative trait loci, etiology
- MeSH terms
- Endocytosis, Humans, Parkinson Disease, Risk Factors, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Mendelian Randomization Analysis
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