Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick van der Spek, Hannah A. Pliner, Shankaracharya [Unknown], Bradley N. Smith, Giuseppe MarangiSimon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Francesco O. Logullo, Isabella Simone, Giancarlo Logroscino, Fabrizio Salvi, Ilaria Bartolomei, Giuseppe Borghero, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Pietro Fratta, Isabella Fogh, Safa Al-Sarraj, Claire Troakes, Caroline Vance, Aleksey Shatunov, Ammar Al-Chalabi, Alfredo Iacoangeli, Stephen Newhouse, Chris Shaw, William Sproviero, Christopher E. Shaw, ITALSGEN Consortium, Genomic Translation for ALS Care (GTAC) Consortium, NYGC ALS Consortium, Answer ALS Foundation, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consortium, Ahmad Al Khleifat

Research output: Contribution to journalArticlepeer-review

422 Citations (Scopus)


To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
Original languageEnglish
Pages (from-to)1268
Number of pages1
Issue number6
Early online date21 Mar 2018
Publication statusE-pub ahead of print - 21 Mar 2018


  • ALS
  • KIF5A
  • GWAS
  • WES
  • WGS
  • cargo
  • axonal transport


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