Dataset Information

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

ABSTRACT: 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.

SUBMITTER: Nicolas A

PROVIDER: S-EPMC5867896 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Nicolas Aude A Kenna Kevin P KP Renton Alan E AE Ticozzi Nicola N Faghri Faraz F Chia Ruth R Dominov Janice A JA Kenna Brendan J BJ Nalls Mike A MA Keagle Pamela P Rivera Alberto M AM van Rheenen Wouter W Murphy Natalie A NA van Vugt Joke J F A JJFA Geiger Joshua T JT Van der Spek Rick A RA Pliner Hannah A HA Shankaracharya Smith Bradley N BN Marangi Giuseppe G Topp Simon D SD Abramzon Yevgeniya Y Gkazi Athina Soragia AS Eicher John D JD Kenna Aoife A Mora Gabriele G Calvo Andrea A Mazzini Letizia L Riva Nilo N Mandrioli Jessica J Caponnetto Claudia C Battistini Stefania S Volanti Paolo P La Bella Vincenzo V Conforti Francesca L FL Borghero Giuseppe G Messina Sonia S Simone Isabella L IL Trojsi Francesca F Salvi Fabrizio F Logullo Francesco O FO D'Alfonso Sandra S Corrado Lucia L Capasso Margherita M Ferrucci Luigi L Moreno Cristiane de Araujo Martins CAM Kamalakaran Sitharthan S Goldstein David B DB Gitler Aaron D AD Harris Tim T Myers Richard M RM Phatnani Hemali H Musunuri Rajeeva Lochan RL Evani Uday Shankar US Abhyankar Avinash A Zody Michael C MC Kaye Julia J Finkbeiner Steven S Wyman Stacia K SK LeNail Alex A Lima Leandro L Fraenkel Ernest E Svendsen Clive N CN Thompson Leslie M LM Van Eyk Jennifer E JE Berry James D JD Miller Timothy M TM Kolb Stephen J SJ Cudkowicz Merit M Baxi Emily E Benatar Michael M Taylor J Paul JP Rampersaud Evadnie E Wu Gang G Wuu Joanne J Lauria Giuseppe G Verde Federico F Fogh Isabella I Tiloca Cinzia C Comi Giacomo P GP Sorarù Gianni G Cereda Cristina C Corcia Philippe P Laaksovirta Hannu H Myllykangas Liisa L Jansson Lilja L Valori Miko M Ealing John J Hamdalla Hisham H Rollinson Sara S Pickering-Brown Stuart S Orrell Richard W RW Sidle Katie C KC Malaspina Andrea A Hardy John J Singleton Andrew B AB Johnson Janel O JO Arepalli Sampath S Sapp Peter C PC McKenna-Yasek Diane D Polak Meraida M Asress Seneshaw S Al-Sarraj Safa S King Andrew A Troakes Claire C Vance Caroline C de Belleroche Jacqueline J Baas Frank F Ten Asbroek Anneloor L M A ALMA Muñoz-Blanco José Luis JL Hernandez Dena G DG Ding Jinhui J Gibbs J Raphael JR Scholz Sonja W SW Floeter Mary Kay MK Campbell Roy H RH Landi Francesco F Bowser Robert R Pulst Stefan M SM Ravits John M JM MacGowan Daniel J L DJL Kirby Janine J Pioro Erik P EP Pamphlett Roger R Broach James J Gerhard Glenn G Dunckley Travis L TL Brady Christopher B CB Kowall Neil W NW Troncoso Juan C JC Le Ber Isabelle I Mouzat Kevin K Lumbroso Serge S Heiman-Patterson Terry D TD Kamel Freya F Van Den Bosch Ludo L Baloh Robert H RH Strom Tim M TM Meitinger Thomas T Shatunov Aleksey A Van Eijk Kristel R KR de Carvalho Mamede M Kooyman Maarten M Middelkoop Bas B Moisse Matthieu M McLaughlin Russell L RL Van Es Michael A MA Weber Markus M Boylan Kevin B KB Van Blitterswijk Marka M Rademakers Rosa R Morrison Karen E KE Basak A Nazli AN Mora Jesús S JS Drory Vivian E VE Shaw Pamela J PJ Turner Martin R MR Talbot Kevin K Hardiman Orla O Williams Kelly L KL Fifita Jennifer A JA Nicholson Garth A GA Blair Ian P IP Rouleau Guy A GA Esteban-Pérez Jesús J García-Redondo Alberto A Al-Chalabi Ammar A Rogaeva Ekaterina E Zinman Lorne L Ostrow Lyle W LW Maragakis Nicholas J NJ Rothstein Jeffrey D JD Simmons Zachary Z Cooper-Knock Johnathan J Brice Alexis A Goutman Stephen A SA Feldman Eva L EL Gibson Summer B SB Taroni Franco F Ratti Antonia A Gellera Cinzia C Van Damme Philip P Robberecht Wim W Fratta Pietro P Sabatelli Mario M Lunetta Christian C Ludolph Albert C AC Andersen Peter M PM Weishaupt Jochen H JH Camu William W Trojanowski John Q JQ Van Deerlin Vivianna M VM Brown Robert H RH van den Berg Leonard H LH Veldink Jan H JH Harms Matthew B MB Glass Jonathan D JD Stone David J DJ Tienari Pentti P Silani Vincenzo V Chiò Adriano A Shaw Christopher E CE Traynor Bryan J BJ Landers John E JE

Neuron 20180301 6

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 causat ...[more]

PMID: 29566793

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Project description:BackgroundCluster headache is a highly debilitating neurological disorder with considerable inter-ethnic differences. Genome-wide association studies (GWAS) recently identified replicable genomic loci for cluster headache in Europeans, but the genetic underpinnings for cluster headache in Asians remain unclear. The objective of this study is to investigate the genetic architecture and susceptibility loci of cluster headache in Han Chinese resided in Taiwan.MethodsWe conducted a two-stage genome-wide association study in a Taiwanese cohort enrolled from 2007 through 2022 to identify the genetic variants associated with cluster headache. Diagnosis of cluster headache was retrospectively ascertained with the criteria of International Classification of Headache Disorders, third edition. Control subjects were enrolled from the Taiwan Biobank. Genotyping was conducted with the Axiom Genome-Wide Array TWB chip, followed by whole genome imputation. A polygenic risk score was developed to differentiate patients from controls. Downstream analyses including gene-set and tissue enrichment, linkage disequilibrium score regression, and pathway analyses were performed.ResultsWe enrolled 734 patients with cluster headache and 9,846 population-based controls. We identified three replicable loci, with the lead SNPs being rs1556780 in CAPN2 (odds ratio = 1.59, 95% CI 1.42‒1.78, p = 7.61 × 10-16), rs10188640 in MERTK (odds ratio = 1.52, 95% CI 1.33‒1.73, p = 8.58 × 10-13), and rs13028839 in STAB2 (odds ratio = 0.63, 95% CI 0.52‒0.78, p = 2.81 × 10-8), with the latter two replicating the findings in European populations. Several previously reported genes also showed significant associations with cluster headache in our samples. Polygenic risk score differentiated patients from controls with an area under the receiver operating characteristic curve of 0.77. Downstream analyses implicated circadian regulation and immunological processes in the pathogenesis of cluster headache.ConclusionsThis study revealed the genetic architecture and novel susceptible loci of cluster headache in Han Chinese residing in Taiwan. Our findings support the common genetic contributions of cluster headache across ethnicities and provide novel mechanistic insights into the pathogenesis of cluster headache.

Dataset Information

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Publications

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

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