RT Journal Article
SR Electronic
T1 Parkinson’s disease genetics: identifying novel risk loci, providing causal insights and improving estimates of heritable risk
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 388165
DO 10.1101/388165
A1 Mike A. Nalls
A1 Cornelis Blauwendraat
A1 Costanza L. Vallerga
A1 Karl Heilbron
A1 Sara Bandres-Ciga
A1 Diana Chang
A1 Manuela Tan
A1 Demis A. Kia
A1 Alastair J. Noyce
A1 Angli Xue
A1 Jose Bras
A1 Emily Young
A1 Rainer von Coelln
A1 Javier Simón-Sánchez
A1 Claudia Schulte
A1 Manu Sharma
A1 Lynne Krohn
A1 Lasse Pihlstrom
A1 Ari Siitonen
A1 Hirotaka Iwaki
A1 Hampton Leonard
A1 Faraz Faghri
A1 J. Raphael Gibbs
A1 Dena G. Hernandez
A1 Sonja W. Scholz
A1 Juan A. Botia
A1 Maria Martinez
A1 Jean-Chrstophe Corvol
A1 Suzanne Lesage
A1 Joseph Jankovic
A1 Lisa M. Shulman
A1 The 23andMe Research Team
A1 System Genomics of Parkinson’s Disease (SGPD) Consortium, Margaret Sutherland
A1 Pentti Tienari
A1 Kari Majamaa
A1 Mathias Toft
A1 Alexis Brice
A1 Jian Yang
A1 Ziv Gan-Or
A1 Thomas Gasser
A1 Peter Heutink
A1 Joshua M Shulman
A1 Nicolas Wood
A1 David A. Hinds
A1 John Hardy
A1 Huw R Morris
A1 Jacob Gratten
A1 Peter M. Visscher
A1 Robert R. Graham
A1 Andrew B. Singleton
A1 for the International Parkinson’s Disease Genomics Consortium.
YR 2018
UL http://biorxiv.org/content/early/2018/08/09/388165.abstract
AB We performed the largest genetic study of Parkinson’s disease to date, involving analysis of 11.4M SNPs in 37.7K cases, 18.6K ‘proxy-cases’ and 1.4M controls, discovering 39 novel risk loci. In total, we identified 92 putative independent genome-wide significant signals including 53 at previously published loci. Next, we dissected risk within these loci, identifying 22 candidate independent risk variants in close proximity to one another representing multiple risk signals in one locus (20 variants proximal to known risk loci). We then employed tests of causality within a Mendelian randomization framework to infer functional genomic consequences for genes within loci of interest in concert with protein-centric network analyses to nominate likely candidates for follow-up investigation. This report also shows expression network signatures of PD loci to be heavily brain enriched and different in comparison to Alzheimer’s disease. We also used risk scoring methods to improve genetic predictions of disease risk, and show that GWAS signals explain 11-15% of the heritable risk of PD at thresholds below genome-wide significance. Additionally, these data also suggest genetic correlations relating to risk overlapping with brain morphology, smoking status and educational attainment. Further analyses of smoking initiation and cognitive performance relating to PD risk in more comprehensive datasets show complex etiological links between PD risk and these traits. These data in sum provide the most comprehensive understanding of the genetic architecture of PD to date, revealing a large number of additional loci, and demonstrating that there remains a considerable genetic component of this disease that has not yet been discovered.See supplemental materials (Text S2).