141624 20240618100105.0 pmc:PMC8422160 pmc 10.1016/S1474-4422(19)30320-5 doi pmid:31701892 pmid 1474-4422 ISSN 1474-4465 ISSN altmetric:69886855 altmetric DZNE-2020-07948 English 610 Nalls, Mike A P:(DE-HGF)0 0 Corresponding author Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. London 2019 Lancet Publ. Group print Crossref Elsevier BV 2019-12-01 article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1718697595_13421 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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). 899H - Addenda (POF3-899H) G:(DE-HGF)POF3-899H POF3-899H POF III 0 2019-12-01 Crossref https://www.elsevier.com/tdm/userlicense/1.0/ Dataset connected to CrossRef, PubMed, Databases, Genetic MeSH Genetic Loci: genetics MeSH Genetic Predisposition to Disease: epidemiology MeSH Genetic Predisposition to Disease: genetics MeSH Genome-Wide Association Study: methods MeSH Humans MeSH Parkinson Disease: diagnosis MeSH Parkinson Disease: epidemiology MeSH Parkinson Disease: genetics MeSH Risk Factors MeSH Blauwendraat, Cornelis P:(DE-HGF)0 1 Vallerga, Costanza L 2 Heilbron, Karl 3 Bandres-Ciga, Sara 4 Chang, Diana 5 Tan, Manuela 6 Kia, Demis A 7 Noyce, Alastair J 8 Xue, Angli 9 Bras, Jose 10 Young, Emily 11 von Coelln, Rainer 12 Simon Sanchez, Javier P:(DE-2719)2811198 13 dzne Schulte, Claudia P:(DE-HGF)0 14 Sharma, Manu P:(DE-HGF)0 15 Krohn, Lynne 16 Pihlstrøm, Lasse 17 Siitonen, Ari 18 Iwaki, Hirotaka 19 Leonard, Hampton 20 Faghri, Faraz 21 Gibbs, J Raphael 22 Hernandez, Dena G P:(DE-HGF)0 23 Scholz, Sonja W 24 Botia, Juan A 25 Martinez, Maria 26 Corvol, Jean-Christophe 27 Lesage, Suzanne 28 Jankovic, Joseph 29 Shulman, Lisa M 30 Sutherland, Margaret 31 Tienari, Pentti 32 Majamaa, Kari 33 Toft, Mathias 34 Andreassen, Ole A P:(DE-HGF)0 35 Bangale, Tushar 36 Brice, Alexis 37 Yang, Jian 38 Gan-Or, Ziv 39 Gasser, Thomas P:(DE-2719)2320009 40 dzne Heutink, Peter P:(DE-2719)2810728 41 dzne Shulman, Joshua M 42 Wood, Nicholas W 43 Hinds, David A 44 Hardy, John A 45 Morris, Huw R 46 Gratten, Jacob 47 Visscher, Peter M 48 Graham, Robert R 49 Singleton, Andrew B 50 Team, 23andMe Research 51 Consortium, System Genomics of Parkinson's Disease 52 Consortium, International Parkinson's Disease Genomics 53 Adarmes-Gómez, Astrid D 54 Aguilar, Miquel 55 Aitkulova, Akbota 56 Akhmetzhanov, Vadim 57 Alcalay, Roy N 58 Alvarez, Ignacio 59 Alvarez, Victoria 60 Bandres-Ciga, Sara 61 Barrero, Francisco Javier 62 Bergareche Yarza, Jesús Alberto 63 Bernal-Bernal, Inmaculada 64 Billingsley, Kimberley 65 Blauwendraat, Cornelis P:(DE-HGF)0 66 Blazquez, Marta 67 Bonilla-Toribio, Marta 68 Botía, Juan A 69 Boungiorno, María Teresa 70 Bras, Jose 71 Brice, Alexis 72 Brockmann, Kathrin P:(DE-HGF)0 73 Bubb, Vivien 74 Buiza-Rueda, Dolores 75 Cámara, Ana 76 Carrillo, Fátima 77 Carrión-Claro, Mario 78 Cerdan, Debora 79 Chelban, Viorica 80 Clarimón, Jordi 81 Clarke, Carl 82 Compta, Yaroslau 83 Cookson, Mark R 84 Corvol, Jean-Christophe 85 Craig, David W 86 Danjou, Fabrice 87 Diez-Fairen, Monica 88 Dols-Icardo, Oriol 89 Duarte, Jacinto 90 Duran, Raquel 91 Escamilla-Sevilla, Francisco 92 Escott-Price, Valentina 93 Ezquerra, Mario 94 Faghri, Faraz 95 Feliz, Cici 96 Fernández, Manel 97 Fernández-Santiago, Rubén P:(DE-HGF)0 98 Finkbeiner, Steven 99 Foltynie, Thomas 100 Gan-Or, Ziv 101 Garcia, Ciara 102 García-Ruiz, Pedro 103 Gibbs, J Raphael 104 Gomez Heredia, Maria Jose 105 Gómez-Garre, Pilar 106 González, Manuel Menéndez 107 Gonzalez-Aramburu, Isabel 108 Guelfi, Sebastian 109 Guerreiro, Rita 110 Hardy, John 111 Hassin-Baer, Sharon 112 Hernandez, Dena G P:(DE-HGF)0 113 Hoenicka, Janet 114 Holmans, Peter 115 Houlden, Henry 116 Infante, Jon 117 Iwaki, Hirotaka 118 Jesús, Silvia 119 Jimenez-Escrig, Adriano 120 Kaishybayeva, Gulnaz 121 Kaiyrzhanov, Rauan 122 Karimova, Altynay 123 Kia, Demis A 124 Kinghorn, Kerri J 125 Koks, Sulev 126 Krohn, Lynne 127 Kulisevsky, Jaime 128 Labrador-Espinosa, Miguel A 129 Leonard, Hampton L 130 Lesage, Suzanne 131 Lewis, Patrick 132 Lopez-Sendon, Jose Luis 133 Lovering, Ruth 134 Lubbe, Steven 135 Lungu, Codrin 136 Macias, Daniel 137 Majamaa, Kari 138 Manzoni, Claudia 139 Marín, Juan 140 Marinus, Johan 141 Marti, Maria Jose 142 Martinez, Maria 143 Martínez Torres, Irene 144 Martínez-Castrillo, Juan Carlos 145 Mata, Marina 146 Mencacci, Niccolo E 147 Méndez-Del-Barrio, Carlota 148 Middlehurst, Ben 149 Mínguez, Adolfo 150 Mir, Pablo 151 Mok, Kin Y 152 Morris, Huw R 153 Muñoz, Esteban 154 Nalls, Mike A 155 Narendra, Derek 156 Noyce, Alastair J 157 Ojo, Oluwadamilola O 158 Okubadejo, Njideka U 159 Pagola, Ana Gorostidi 160 Pastor, Pau 161 Perez Errazquin, Francisco 162 Periñán-Tocino, Teresa 163 Pihlstrom, Lasse 164 Plun-Favreau, Helene 165 Quinn, John 166 R'Bibo, Lea 167 Reed, Xylena 168 Rezola, Elisabet Mondragon 169 Rizig, Mie 170 Rizzu, Patrizia P:(DE-HGF)0 171 Robak, Laurie 172 Rodriguez, Antonio Sanchez 173 Rouleau, Guy A 174 Ruiz-Martínez, Javier 175 Ruz, Clara 176 Ryten, Mina 177 Sadykova, Dinara 178 Scholz, Sonja W 179 Schreglmann, Sebastian 180 Schulte, Claudia P:(DE-HGF)0 181 Sharma, Manu P:(DE-HGF)0 182 Shashkin, Chingiz 183 Shulman, Joshua M 184 Sierra, María 185 Siitonen, Ari 186 Singleton, Andrew B 187 Suarez-Sanmartin, Esther 188 Taba, Pille 189 Tabernero, Cesar 190 Tan, Manuela X 191 Tartari, Juan Pablo 192 Tejera-Parrado, Cristina 193 Toft, Mathias 194 Tolosa, Eduard 195 Trabzuni, Daniah 196 Valldeoriola, Francesc 197 van Hilten, Jacobus J 198 Van Keuren-Jensen, Kendall 199 Vargas-González, Laura 200 Vela, Lydia 201 Vives, Francisco 202 Williams, Nigel 203 Wood, Nicholas W 204 Zharkinbekova, Nazira 205 Zharmukhanov, Zharkyn 206 Zholdybayeva, Elena 207 Zimprich, Alexander 208 Ylikotila, Pauli 209 Shulman, Lisa M 210 von Coelln, Rainer 211 Reich, Stephen 212 Savitt, Joseph 213 Agee, Michelle 214 Alipanahi, Babak 215 Auton, Adam 216 Bell, Robert K 217 Bryc, Katarzyna 218 Elson, Sarah L 219 Fontanillas, Pierre 220 Furlotte, Nicholas A 221 Huber, Karen E 222 Hicks, Barry 223 Jewett, Ethan M 224 Jiang, Yunxuan 225 Kleinman, Aaron 226 Lin, Keng-Han 227 Litterman, Nadia K 228 McCreight, Jennifer C 229 McIntyre, Matthew H 230 McManus, Kimberly F 231 Mountain, Joanna L 232 Noblin, Elizabeth S 233 Northover, Carrie A M 234 Pitts, Steven J 235 Poznik, G David 236 Sathirapongsasuti, J Fah 237 Shelton, Janie F 238 Shringarpure, Suyash 239 Tian, Chao 240 Tung, Joyce 241 Vacic, Vladimir 242 Wang, Xin 243 Wilson, Catherine H 244 Anderson, Tim 245 Bentley, Steven 246 Dalrymple-Alford, John 247 Fowdar, Javed 248 Gratten, Jacob 249 Halliday, Glenda 250 Henders, Anjali K 251 Hickie, Ian 252 Kassam, Irfahan 253 Kennedy, Martin 254 Kwok, John 255 Lewis, Simon 256 Mellick, George 257 Montgomery, Grant 258 Pearson, John 259 Pitcher, Toni 260 Sidorenko, Julia 261 Silburn, Peter A 262 Vallerga, Costanza L 263 Visscher, Peter M 264 Wallace, Leanne 265 Wray, Naomi R 266 Xue, Angli 267 Yang, Jian 268 Zhang, Futao 269 10.1016/s1474-4422(19)30320-5 : Elsevier BV, 2019-12-01 12 1091-1102 journal-article Crossref The Lancet Neurology 18 2019 1474-4422 10.1016/S1474-4422(19)30320-5 Vol. 18, no. 12, p. 1091 - 1102 PERI:(DE-600)2079704-7 12 18:12<1091 - 1102 1091-1102 The lancet <London> / 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