Format

Send to

Choose Destination
Mov Disord. 2019 Apr;34(4):460-468. doi: 10.1002/mds.27614. Epub 2019 Jan 24.

The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease.

Collaborators (136)

Noyce AJ, Kaiyrzhanov R, Middlehurst B, Kia DA, Tan M, Houlden H, Morris HR, Plun-Favreau H, Holmans P, Hardy J, Trabzuni D, Bras J, Quinn J, Mok KY, Kinghorn KJ, Billingsley K, Wood NW, Lewis P, Schreglmann S, Guerreiro R, Lovering R, RņBibo L, Rizig M, Ryten M, Guelfi S, Escott-Price V, Chelban V, Williams N, Morrison KE, Brice A, Danjou F, Lesage S, Corvol JC, Martinez M, Schulte C, Brockmann K, SimɃn-Sȥnchez J, Heutink P, Rizzu P, Sharma M, Gasser T, Nicolas A, Cookson MR, Bandres-Ciga S, Blauwendraat C, Craig DW, Faghri F, Gibbs JR, Hernandez DG, Shulman JM, Iwaki H, Leonard HL, Nalls MA, Robak L, Lubbe S, Finkbeiner S, Mencacci NE, Singleton AB, Reed X, Alcalay RN, Gan-Or Z, Rouleau GA, van Hilten JJ, Adarmes-GɃmez AD, Aguilar M, Alvarez I, Alvarez V, Barrero FJ, Yarza JAB, Bernal-Bernal I, Blazquez M, Bonilla-Toribio M, Botȷa JA, Boungiorno MT, Buiza-Rueda D, Cȥmara A, Carrillo F, CarriɃn-Claro M, Cerdan D, ClarimɃn J, Compta Y, de la Casa B, Diez-Fairen M, Dols-Icardo O, Duarte J, Duran R, Escamilla-Sevilla F, Ezquerra M, Feliz C, Fernȥndez M, Fernȥndez-Santiago R, Garcia C, Garcȷa-Ruiz P, GɃmez-Garre P, Heredia MJG, Pagola AG, Infante J, Jimenez-Escrig A, Kulisevsky J, Labrador-Espinosa MA, Lopez-Sendon JL, de Munain Arregui AL, Torres IM, Marȷn J, Marti MJ, Martȷnez-Castrillo JC, Mȳndez-Del-Barrio C, Gonzȥlez MM, Mata M, Mȷnguez A, Mir P, Rezola EM, MuɁoz E, Pagonabarraga J, Pascual-Sedano B, Pastor P, Errazquin FP, PeriɁȥn-Tocino T, Ruiz-Martȷnez J, Ruz C, Rodriguez AS, Sierra M, Suarez-Sanmartin E, Tabernero C, Tartari JP, Tejera-Parrado C, Tolosa E, Valldeoriola F, Vargas-Gonzȥlez L, Vela L, Zimprich A, Pihlstrom L, Toft M, Koks S, Taba P, Hassin-Baer S.

Author information

1
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
2
Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain.
3
Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
4
Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
5
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
6
Department of Pathophysiology, University of Tartu, Tartu, Estonia.
7
Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
8
Department of Neurology, Oslo University Hospital, Oslo, Norway.
9
Department of Neurology and Neurosurgery, Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
10
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
11
Data Tecnica International, Glen Echo, Maryland, USA.

Abstract

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.

KEYWORDS:

Parkinson's disease; endocytosis; genetic risk; heritability; polygenic risk score

PMID:
30675927
PMCID:
PMC6467788
[Available on 2020-04-01]
DOI:
10.1002/mds.27614

Supplemental Content

Full text links

Icon for Wiley Icon for Norwegian BIBSYS system
Loading ...
Support Center