作者
Yi-Jun Ge,Ya‐Nan Ou,Yue‐Ting Deng,Bang‐Sheng Wu,Yang Liu,Yaru Zhang,Shi-Dong Chen,Yu‐Yuan Huang,Qiang Dong,Lan Tan,Jin‐Tai Yu,Raffaele Ferrari,Dena G. Hernandez,Michael A. Nalls,Jonathan D. Rohrer,Adaikalavan Ramasamy,John B. Kwok,Carol Dobson‐Stone,William S. Brooks,Peter R. Schofield,Glenda M. Halliday,John R. Hodges,Olivier Piguet,Lauren Bartley,Elizabeth Thompson,Eric Haan,Isabel Hernández,Agustín Ruíz,Merçé Boada,Barbara Borroni,Alessandro Padovani,Carlos Cruchaga,Nigel J. Cairns,Luisa Benussi,Giuliano Binetti,Roberta Ghidoni,Gianluigi Forloni,Daniela Galimberti,Chiara Fenoglio,María Serpente,Elio Scarpini,Jordi Clarimón,Alberto Lleó,Rafael Blesa,María Landqvist Waldö,Karin Nilsson,Christer Nilsson,Ian R. Mackenzie,Ging‐Yuek Robin Hsiung,David Mann,Jordan Grafman,Christopher Morris,Johannes Attems,Timothy D. Griffiths,Ian McKeith,Alan Thomas,Pietro Pietrini,Edward D. Huey,Eric M. Wassermann,Atik Baborie,Evelyn Jaros,Michael Tierney,Pau Pástor,Cristina Razquín,Sara Ortega‐Cubero,Elena Alonso,Robert Perneczky,Janine Diehl‐Schmid,Panagiotis Alexopoulos,Alexander Kurz,Innocenzo Rainero,Elisa Rubino,Lorenzo Pinessi,Ekaterina Rogaeva,Peter St George‐Hyslop,Giacomina Rossi,Fabrizio Tagliavini,Giorgio Giaccone,James B. Rowe,J Schlachetzki,James Uphill,John Collinge,Simon Mead,Adrian Danek,Vivianna M. Van Deerlin,Murray Grossman,John Q. Trojanowski,Julie van der Zee,William Deschamps,Tim Van Langenhove,Marc Cruts,Christine Van Broeckhoven,Stefano F. Cappa,Isabelle Le Ber,Didier Hannequin,Véronique Golfier,Martine Vercelletto,Alexis Brice,Benedetta Nacmias,Sandro Sorbi,Silvia Bagnoli,Irene Piaceri,Jørgen E. Nielsen,Lena E. Hjermind,Matthias Riemenschneider,Manuel Mayhaus,Bernd Ibach,Gilles Gasparoni,Sabrina Pichler,Wei Gu,Martin N. Rossor,Nick C. Fox,Jason D. Warren,Maria Grazia Spillantini,Huw Morris,Patrizia Rizzu,Peter Heutink,Julie S. Snowden,Sara Rollinson,Anna Richardson,Alexander Gerhard,Amalia C. Bruni,Raffaele Maletta,Francesca Frangipane,Chiara Cupidi,Livia Bernardi,Maria Anfossi,Maura Gallo,Maria Elena Conidi,Nicoletta Smirne,Rosa Rademakers,Matt Baker,Dennis W. Dickson,Neill R. Graff‐Radford,Ronald C. Petersen,David S. Knopman,Keith A. Josephs,Bradley F. Boeve,Joseph E. Parisi,William W. Seeley,Bruce L. Miller,Anna Karydas,Howard J. Rosen,John C. van Swieten,Elise G.P. Dopper,Harro Seelaar,Yolande A.L. Pijnenburg,Philip Scheltens,Giancarlo Logroscino,Rosa Capozzo,Valeria Novelli,Annibale Alessandro Puca,M. Franceschi,Alfredo Postiglione,Graziella Milan,Paolo Sorrentino,Mark Kristiansen,Huei‐Hsin Chiang,Caroline Graff,Florence Pasquier,Adeline Rollin,Vincent Deramecourt,Florence Lebert,Dimitrios Kapogiannis,Luigi Ferrucci,Stuart Pickering‐Brown,Andrew Singleton,John Hardy,Parastoo Momeni
摘要
Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases.We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci identified from one genome-wide association study with 376 participants and another with 3301 participants, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated.Our analyses showed targeting BIN1, GRN, and RET levels in blood as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce Alzheimer's disease risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for Parkinson's disease. Among them, GPNMB was the most promising target for Parkinson's disease with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, and MAPK3 in blood and DHRS11, FAM120B, SHMT1, and TSFM in brain might affect multiple sclerosis risk. The risk of amyotrophic lateral sclerosis might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain.Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets.