Author:
Nalls Mike A.,Blauwendraat Cornelis,Vallerga Costanza L.,Heilbron Karl,Bandres-Ciga Sara,Chang Diana,Tan Manuela,Kia Demis A.,Noyce Alastair J.,Xue Angli,Bras Jose,Young Emily,von Coelln Rainer,Simón-Sánchez Javier,Schulte Claudia,Sharma Manu,Krohn Lynne,Pihlstrom Lasse,Siitonen Ari,Iwaki Hirotaka,Leonard Hampton,Faghri Faraz,Raphael Gibbs J.,Hernandez Dena G.,Scholz Sonja W.,Botia Juan A.,Martinez Maria,Corvol Jean-Christophe,Lesage Suzanne,Jankovic Joseph,Shulman Lisa M.,Sutherland Margaret,Tienari Pentti,Majamaa Kari,Toft Mathias,Andreassen Ole A.,Bangale Tushar,Brice Alexis,Yang Jian,Gan-Or Ziv,Gasser Thomas,Heutink Peter,Shulman Joshua M,Wood Nicolas,Hinds David A.,Hardy John A.,Morris Huw R,Gratten Jacob,Visscher Peter M.,Graham Robert R.,Singleton Andrew B., , ,
Abstract
AbstractWe performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.
Publisher
Cold Spring Harbor Laboratory