• Frank P Diekstra, Vivianna M Van Deerlin, John C van Swieten, Ammar Al-Chalabi, Albert C Ludolph, Jochen H Weishaupt, Orla Hardiman, John E Landers, Robert H Brown, Michael A van Es, R Jeroen Pasterkamp, Max Koppers, Peter M Andersen, Karol Estrada, Fernando Rivadeneira, Albert Hofman, André G Uitterlinden, Philip van Damme, Judith Melki, Vincent Meininger, Aleksey Shatunov, Christopher E Shaw, P Nigel Leigh, Pamela J Shaw, Karen E Morrison, Isabella Fogh, Adriano Chiò, Bryan J Traynor, David Czell, Markus Weber, Peter Heutink, Paul I W de Bakker, Vincenzo Silani, Wim Robberecht, Leonard H van den Berg, and Jan H Veldink.
• Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
• Ann. Neurol. 2014 Jul 1;76(1):120-33.

ObjectiveSubstantial 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.MethodsWe 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.ResultsMeta-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) ).InterpretationWe 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.© 2014 American Neurological Association.

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