UNC13A is a modifier of survival in amyotrophic lateral sclerosis

Diekstra, Frank P.; van Vught, Paul W.J.; van Rheenen, Wouter; Koppers, Max; Pasterkamp, R. Jeroen; van Es, Michael A.; Schelhaas, Helenius J.; de Visser, Marianne; Robberecht, Wim; Van Damme, Philip; Andersen, Peter M.; van den Berg, Leonard H.; Veldink, Jan H.

doi:10.1016/j.neurobiolaging.2011.10.029

« Previous Next »Neurobiology of Aging
Volume 33, Issue 3 , Pages 630.e3-630.e8, March 2012

UNC13A is a modifier of survival in amyotrophic lateral sclerosis

Frank P. Diekstra
- Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
Paul W.J. van Vught
- Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
Wouter van Rheenen
- Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
Max Koppers
- Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
R. Jeroen Pasterkamp
- Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands
Michael A. van Es
- Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
Helenius J. Schelhaas
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, 6500 HB, Nijmegen, The Netherlands
Marianne de Visser
- Department of Neurology, Academic Medical Center, 1100 DD, Amsterdam, The Netherlands
Wim Robberecht
- Department of Neurology, University Hospital Leuven, University of Leuven, 3000 Leuven, Belgium
- Laboratory for Neurobiology, Vesalius Research Centre, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium
Philip Van Damme
- Department of Neurology, University Hospital Leuven, University of Leuven, 3000 Leuven, Belgium
- Laboratory for Neurobiology, Vesalius Research Centre, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium
Peter M. Andersen
- Department of Clinical Neuroscience, Umeå University, SE-901 85 Umeå, Sweden
Leonard H. van den Berg
- Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
- These authors contributed equally to the manuscript.
Jan H. Veldink
- Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
- These authors contributed equally to the manuscript.
- Corresponding author at: Department of Neurology, G03.228, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Tel.: +31 88 7557939; fax: +31 30 2542100

Received 5 July 2011; received in revised form 18 October 2011; accepted 24 October 2011. published online 28 November 2011.

Abstract

A large genome-wide screen in patients with sporadic amyotrophic lateral sclerosis (ALS) showed that the common variant rs12608932 in gene UNC13A was associated with disease susceptibility. UNC13A regulates the release of neurotransmitters, including glutamate. Genetic risk factors that, in addition, modify survival, provide promising therapeutic targets in ALS, a disease whose etiology remains largely elusive. We examined whether UNC13A was associated with survival of ALS patients in a cohort of 450 sporadic ALS patients and 524 unaffected controls from a population-based study of ALS in The Netherlands. Additionally, survival data were collected from individuals of Dutch, Belgian, or Swedish descent (1767 cases, 1817 controls) who had participated in a previously published genome-wide association study of ALS. We related survival to rs12608932 genotype. In both cohorts, the minor allele of rs12608932 in UNC13A was not only associated with susceptibility but also with shorter survival of ALS patients. Our results further corroborate the role of UNC13A in ALS pathogenesis.

Keywords: Amyotrophic lateral sclerosis (ALS) , UNC13A , rs12608932 , Survival