C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis

Diekstra, Frank P, Van Deerlin, Vivianna M, van Swieten, John C, Al-Chalabi, Ammar, Ludolph, Albert C, Weishaupt, Jochen H, Hardiman, Orla, Landers, John E, Brown, Robert H, van Es, Michael A, Pasterkamp, R Jeroen, Koppers, Max, Andersen, Peter M, Estrada, Karol, Rivadeneira, Fernando, Hofman, Albert, Uitterlinden, André G, van Damme, Philip, Melki, Judith, Meininger, Vincent, Shatunov, Aleksey, Shaw, Christopher E, Leigh, P Nigel, Shaw, Pamela J, Morrison, Karen E, Fogh, Isabella, Chiò, Adriano, Traynor, Bryan J, Czell, David, Weber, Markus, Heutink, Peter, de Bakker, Paul I W, Silani, Vincenzo, Robberecht, Wim, van den Berg, Leonard H and Veldink, Jan H (2014) C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis. Annals of Neurology, 76 (1). pp. 120-33. ISSN 0364-5134

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Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD.


We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes.


Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10(-12) ) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10(-11) ) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10(-7) ) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10(-7) ).


We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
Subjects: R Medicine
R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0346 Neurology. Diseases of the nervous system Including speech disorders
Depositing User: Patricia Butler
Date Deposited: 26 Nov 2015 15:02
Last Modified: 25 Jul 2017 14:53
URI: http://sro.sussex.ac.uk/id/eprint/54193
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