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@ARTICLE{Nalls:141624,
author = {Nalls, Mike A and Blauwendraat, Cornelis and Vallerga,
Costanza L and Heilbron, Karl and Bandres-Ciga, Sara and
Chang, Diana and Tan, Manuela and Kia, Demis A and Noyce,
Alastair J and Xue, Angli and Bras, Jose and Young, Emily
and von Coelln, Rainer and Simon Sanchez, Javier and
Schulte, Claudia and Sharma, Manu and Krohn, Lynne and
Pihlstrøm, Lasse and Siitonen, Ari and Iwaki, Hirotaka and
Leonard, Hampton and Faghri, Faraz and Gibbs, J Raphael and
Hernandez, Dena G and Scholz, Sonja W and Botia, Juan A and
Martinez, Maria and Corvol, Jean-Christophe and Lesage,
Suzanne and Jankovic, Joseph and Shulman, Lisa M and
Sutherland, Margaret and Tienari, Pentti and Majamaa, Kari
and Toft, Mathias and Andreassen, Ole A and Bangale, Tushar
and Brice, Alexis and Yang, Jian and Gan-Or, Ziv and Gasser,
Thomas and Heutink, Peter and Shulman, Joshua M and Wood,
Nicholas W and Hinds, David A and Hardy, John A and Morris,
Huw R and Gratten, Jacob and Visscher, Peter M and Graham,
Robert R and Singleton, Andrew B and Team, 23andMe Research
and Consortium, System Genomics of Parkinson's Disease and
Consortium, International Parkinson's Disease Genomics and
Adarmes-Gómez, Astrid D and Aguilar, Miquel and Aitkulova,
Akbota and Akhmetzhanov, Vadim and Alcalay, Roy N and
Alvarez, Ignacio and Alvarez, Victoria and Bandres-Ciga,
Sara and Barrero, Francisco Javier and Bergareche Yarza,
Jesús Alberto and Bernal-Bernal, Inmaculada and
Billingsley, Kimberley and Blauwendraat, Cornelis and
Blazquez, Marta and Bonilla-Toribio, Marta and Botía, Juan
A and Boungiorno, María Teresa and Bras, Jose and Brice,
Alexis and Brockmann, Kathrin and Bubb, Vivien and
Buiza-Rueda, Dolores and Cámara, Ana and Carrillo, Fátima
and Carrión-Claro, Mario and Cerdan, Debora and Chelban,
Viorica and Clarimón, Jordi and Clarke, Carl and Compta,
Yaroslau and Cookson, Mark R and Corvol, Jean-Christophe and
Craig, David W and Danjou, Fabrice and Diez-Fairen, Monica
and Dols-Icardo, Oriol and Duarte, Jacinto and Duran, Raquel
and Escamilla-Sevilla, Francisco and Escott-Price, Valentina
and Ezquerra, Mario and Faghri, Faraz and Feliz, Cici and
Fernández, Manel and Fernández-Santiago, Rubén and
Finkbeiner, Steven and Foltynie, Thomas and Gan-Or, Ziv and
Garcia, Ciara and García-Ruiz, Pedro and Gibbs, J Raphael
and Gomez Heredia, Maria Jose and Gómez-Garre, Pilar and
González, Manuel Menéndez and Gonzalez-Aramburu, Isabel
and Guelfi, Sebastian and Guerreiro, Rita and Hardy, John
and Hassin-Baer, Sharon and Hernandez, Dena G and Hoenicka,
Janet and Holmans, Peter and Houlden, Henry and Infante, Jon
and Iwaki, Hirotaka and Jesús, Silvia and Jimenez-Escrig,
Adriano and Kaishybayeva, Gulnaz and Kaiyrzhanov, Rauan and
Karimova, Altynay and Kia, Demis A and Kinghorn, Kerri J and
Koks, Sulev and Krohn, Lynne and Kulisevsky, Jaime and
Labrador-Espinosa, Miguel A and Leonard, Hampton L and
Lesage, Suzanne and Lewis, Patrick and Lopez-Sendon, Jose
Luis and Lovering, Ruth and Lubbe, Steven and Lungu, Codrin
and Macias, Daniel and Majamaa, Kari and Manzoni, Claudia
and Marín, Juan and Marinus, Johan and Marti, Maria Jose
and Martinez, Maria and Martínez Torres, Irene and
Martínez-Castrillo, Juan Carlos and Mata, Marina and
Mencacci, Niccolo E and Méndez-Del-Barrio, Carlota and
Middlehurst, Ben and Mínguez, Adolfo and Mir, Pablo and
Mok, Kin Y and Morris, Huw R and Muñoz, Esteban and Nalls,
Mike A and Narendra, Derek and Noyce, Alastair J and Ojo,
Oluwadamilola O and Okubadejo, Njideka U and Pagola, Ana
Gorostidi and Pastor, Pau and Perez Errazquin, Francisco and
Periñán-Tocino, Teresa and Pihlstrom, Lasse and
Plun-Favreau, Helene and Quinn, John and R'Bibo, Lea and
Reed, Xylena and Rezola, Elisabet Mondragon and Rizig, Mie
and Rizzu, Patrizia and Robak, Laurie and Rodriguez, Antonio
Sanchez and Rouleau, Guy A and Ruiz-Martínez, Javier and
Ruz, Clara and Ryten, Mina and Sadykova, Dinara and Scholz,
Sonja W and Schreglmann, Sebastian and Schulte, Claudia and
Sharma, Manu and Shashkin, Chingiz and Shulman, Joshua M and
Sierra, María and Siitonen, Ari and Singleton, Andrew B and
Suarez-Sanmartin, Esther and Taba, Pille and Tabernero,
Cesar and Tan, Manuela X and Tartari, Juan Pablo and
Tejera-Parrado, Cristina and Toft, Mathias and Tolosa,
Eduard and Trabzuni, Daniah and Valldeoriola, Francesc and
van Hilten, Jacobus J and Van Keuren-Jensen, Kendall and
Vargas-González, Laura and Vela, Lydia and Vives, Francisco
and Williams, Nigel and Wood, Nicholas W and Zharkinbekova,
Nazira and Zharmukhanov, Zharkyn and Zholdybayeva, Elena and
Zimprich, Alexander and Ylikotila, Pauli and Shulman, Lisa M
and von Coelln, Rainer and Reich, Stephen and Savitt, Joseph
and Agee, Michelle and Alipanahi, Babak and Auton, Adam and
Bell, Robert K and Bryc, Katarzyna and Elson, Sarah L and
Fontanillas, Pierre and Furlotte, Nicholas A and Huber,
Karen E and Hicks, Barry and Jewett, Ethan M and Jiang,
Yunxuan and Kleinman, Aaron and Lin, Keng-Han and Litterman,
Nadia K and McCreight, Jennifer C and McIntyre, Matthew H
and McManus, Kimberly F and Mountain, Joanna L and Noblin,
Elizabeth S and Northover, Carrie A M and Pitts, Steven J
and Poznik, G David and Sathirapongsasuti, J Fah and
Shelton, Janie F and Shringarpure, Suyash and Tian, Chao and
Tung, Joyce and Vacic, Vladimir and Wang, Xin and Wilson,
Catherine H and Anderson, Tim and Bentley, Steven and
Dalrymple-Alford, John and Fowdar, Javed and Gratten, Jacob
and Halliday, Glenda and Henders, Anjali K and Hickie, Ian
and Kassam, Irfahan and Kennedy, Martin and Kwok, John and
Lewis, Simon and Mellick, George and Montgomery, Grant and
Pearson, John and Pitcher, Toni and Sidorenko, Julia and
Silburn, Peter A and Vallerga, Costanza L and Visscher,
Peter M and Wallace, Leanne and Wray, Naomi R and Xue, Angli
and Yang, Jian and Zhang, Futao},
title = {{I}dentification of novel risk loci, causal insights, and
heritable risk for {P}arkinson's disease: a meta-analysis of
genome-wide association studies.},
journal = {The lancet / Neurology},
volume = {18},
number = {12},
issn = {1474-4422},
address = {London},
publisher = {Lancet Publ. Group},
reportid = {DZNE-2020-07948},
pages = {1091-1102},
year = {2019},
abstract = {Genome-wide association studies (GWAS) in Parkinson's
disease have increased the scope of biological knowledge
about the disease over the past decade. We aimed to use the
largest aggregate of GWAS data to identify novel risk loci
and gain further insight into the causes of Parkinson's
disease.We did a meta-analysis of 17 datasets from
Parkinson's disease GWAS available from European ancestry
samples to nominate novel loci for disease risk. These
datasets incorporated all available data. We then used these
data to estimate heritable risk and develop predictive
models of this heritability. We also used large gene
expression and methylation resources to examine possible
functional consequences as well as tissue, cell type, and
biological pathway enrichments for the identified risk
factors. Additionally, we examined shared genetic risk
between Parkinson's disease and other phenotypes of interest
via genetic correlations followed by Mendelian
randomisation.Between Oct 1, 2017, and Aug 9, 2018, we
analysed 7·8 million single nucleotide polymorphisms in
37 688 cases, 18 618 UK Biobank proxy-cases (ie,
individuals who do not have Parkinson's disease but have a
first degree relative that does), and 1·4 million controls.
We identified 90 independent genome-wide significant risk
signals across 78 genomic regions, including 38 novel
independent risk signals in 37 loci. These 90 variants
explained $16-36\%$ of the heritable risk of Parkinson's
disease depending on prevalence. Integrating methylation and
expression data within a Mendelian randomisation framework
identified putatively associated genes at 70 risk signals
underlying GWAS loci for follow-up functional studies.
Tissue-specific expression enrichment analyses suggested
Parkinson's disease loci were heavily brain-enriched, with
specific neuronal cell types being implicated from single
cell data. We found significant genetic correlations with
brain volumes (false discovery rate-adjusted p=0·0035 for
intracranial volume, p=0·024 for putamen volume), smoking
status (p=0·024), and educational attainment (p=0·038).
Mendelian randomisation between cognitive performance and
Parkinson's disease risk showed a robust association
(p=8·00 × 10-7).These data provide the most
comprehensive survey of genetic risk within Parkinson's
disease to date, to the best of our knowledge, by revealing
many additional Parkinson's disease risk loci, providing a
biological context for these risk factors, and showing that
a considerable genetic component of this disease remains
unidentified. These associations derived from European
ancestry datasets will need to be followed-up with more
diverse data.The National Institute on Aging at the National
Institutes of Health (USA), The Michael J Fox Foundation,
and The Parkinson's Foundation (see appendix for full list
of funding sources).},
keywords = {Databases, Genetic / Genetic Loci: genetics / Genetic
Predisposition to Disease: epidemiology / Genetic
Predisposition to Disease: genetics / Genome-Wide
Association Study: methods / Humans / Parkinson Disease:
diagnosis / Parkinson Disease: epidemiology / Parkinson
Disease: genetics / Risk Factors},
cin = {AG Heutink / AG Gasser},
ddc = {610},
cid = {I:(DE-2719)1210002 / I:(DE-2719)1210000},
pnm = {899H - Addenda (POF3-899H)},
pid = {G:(DE-HGF)POF3-899H},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC8422160},
pubmed = {pmid:31701892},
doi = {10.1016/S1474-4422(19)30320-5},
url = {https://pub.dzne.de/record/141624},
}
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