| Title: |
Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies |
| Authors: |
Nalls, MA; Blauwendraat, C; Vallerga, CL; Heilbron, K; Bandres-Ciga, S; Chang, D; Tan, M; Kia, DA; Noyce, AJ; Xue, A; Bras, J; Young, E; von Coelln, R; Simón-Sánchez, J; Schulte, C; Sharma, M; Krohn, L; Pihlstrøm, L; Siitonen, A; Iwaki, H; Leonard, H; Faghri, F; Gibbs, JR; Hernandez, DG; Scholz, SW; Botia, JA; Martinez, M; Corvol, JC; Lesage, S; Jankovic, J; Shulman, LM; Sutherland, M; Tienari, P; Majamaa, K; Toft, M; Andreassen, OA; Bangale, T; Brice, A; Yang, J; Gan-Or, Z; Gasser, T; Heutink, P; Shulman, JM; Wood, NW; Hinds, DA; Hardy, JA; Morris, HR; Gratten, J; Visscher, PM; Graham, RR; Singleton, AB; Adarmes-Gómez, AD; Aguilar, M; Aitkulova, A; Akhmetzhanov, V; Alcalay, RN; Alvarez, I; Alvarez, V; Barrero, FJ; Bergareche Yarza, JA; Bernal-Bernal, I; Billingsley, K; Blazquez, M; Bonilla-Toribio, M; Botía, JA; Boungiorno, MT; Brockmann, K; Bubb, V; Buiza-Rueda, D; Cámara, A; Carrillo, F; Carrión-Claro, M; Cerdan, D; Chelban, V; Clarimón, J; Clarke, C; Compta, Y; Cookson, MR; Craig, DW; Danjou, F; Diez-Fairen, M; Dols-Icardo, O; Duarte, J; Duran, R; Escamilla-Sevilla, F; Escott-Price, V; Ezquerra, M; Feliz, C; Fernández, M; Fernández-Santiago, R; Finkbeiner, S; Foltynie, T; Garcia, C; García-Ruiz, P; Gomez Heredia, MJ; Gómez-Garre, P; González, MM; Gonzalez-Aramburu, I; Guelfi, S; Guerreiro, R |
| Source: |
The Lancet Neurology , 18 (12) pp. 1091-1102. (2019) |
| Publication Year: |
2019 |
| Collection: |
University College London: UCL Discovery |
| Description: |
Background: 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. / Methods: 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. / Findings: 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 ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10085837/1/meta5_acceptedversion.pdf; https://discovery.ucl.ac.uk/id/eprint/10085837/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10085837/1/meta5_acceptedversion.pdf; https://discovery.ucl.ac.uk/id/eprint/10085837/ |
| Rights: |
open |
| Accession Number: |
edsbas.E2299B80 |
| Database: |
BASE |