TY - JOUR T1 - Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk JF - bioRxiv DO - 10.1101/388165 SP - 388165 AU - Mike A. Nalls AU - Cornelis Blauwendraat AU - Costanza L. Vallerga AU - Karl Heilbron AU - Sara Bandres-Ciga AU - Diana Chang AU - Manuela Tan AU - Demis A. Kia AU - Alastair J. Noyce AU - Angli Xue AU - Jose Bras AU - Emily Young AU - Rainer von Coelln AU - Javier Simón-Sánchez AU - Claudia Schulte AU - Manu Sharma AU - Lynne Krohn AU - Lasse Pihlstrom AU - Ari Siitonen AU - Hirotaka Iwaki AU - Hampton Leonard AU - Faraz Faghri AU - J. Raphael Gibbs AU - Dena G. Hernandez AU - Sonja W. Scholz AU - Juan A. Botia AU - Maria Martinez AU - Jean-Christophe Corvol AU - Suzanne Lesage AU - Joseph Jankovic AU - Lisa M. Shulman AU - The 23andMe Research Team AU - System Genomics of Parkinson’s Disease (SGPD) Consortium AU - Margaret Sutherland AU - Pentti Tienari AU - Kari Majamaa AU - Mathias Toft AU - Ole A. Andreassen AU - Tushar Bangale AU - Alexis Brice AU - Jian Yang AU - Ziv Gan-Or AU - Thomas Gasser AU - Peter Heutink AU - Joshua M Shulman AU - Nicolas Wood AU - David A. Hinds AU - John A. Hardy AU - Huw R Morris AU - Jacob Gratten AU - Peter M. Visscher AU - Robert R. Graham AU - Andrew B. Singleton AU - for the International Parkinson’s Disease Genomics Consortium Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/03/04/388165.abstract N2 - We 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. ER -