TY - JOUR
T1 - Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome
AU - International Parkinson's Disease Genomics Consortium (IPDGC)
AU - Storm, Catherine S.
AU - Kia, Demis A.
AU - Almramhi, Mona M.
AU - Bandres-Ciga, Sara
AU - Finan, Chris
AU - Noyce, Alastair J.
AU - Kaiyrzhanov, Rauan
AU - Middlehurst, Ben
AU - Tan, Manuela
AU - Houlden, Henry
AU - Morris, Huw R.
AU - Plun-Favreau, Helene
AU - Holmans, Peter
AU - Hardy, John
AU - Trabzuni, Daniah
AU - Quinn, John
AU - Bubb, Vivien
AU - Mok, Kin Y.
AU - Kinghorn, Kerri J.
AU - Lewis, Patrick
AU - Schreglmann, Sebastian R.
AU - Lovering, Ruth
AU - R’Bibo, Lea
AU - Manzoni, Claudia
AU - Rizig, Mie
AU - Ryten, Mina
AU - Guelfi, Sebastian
AU - Escott-Price, Valentina
AU - Chelban, Viorica
AU - Foltynie, Thomas
AU - Williams, Nigel
AU - Morrison, Karen E.
AU - Clarke, Carl
AU - Harvey, Kirsten
AU - Jacobs, Benjamin M.
AU - Brice, Alexis
AU - Danjou, Fabrice
AU - Lesage, Suzanne
AU - Corvol, Jean Christophe
AU - Martinez, Maria
AU - Schulte, Claudia
AU - Brockmann, Kathrin
AU - Simón-Sánchez, Javier
AU - Heutink, Peter
AU - Rizzu, Patrizia
AU - Sharma, Manu
AU - Gasser, Thomas
AU - Schneider, Susanne A.
AU - Ross, Owen A.
AU - Wszolek, Zbigniew K.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development.
AB - Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development.
UR - http://www.scopus.com/inward/record.url?scp=85121559630&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85121559630&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-26280-1
DO - 10.1038/s41467-021-26280-1
M3 - Article
C2 - 34930919
AN - SCOPUS:85121559630
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 7342
ER -