C9orf72 and UNC13A are shared risk loci for ALS and FTD: A genome-wide meta-analysis

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 MeiningerAleksey 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, Jan H Veldink

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)


Objective: 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.

Methods: We used published GWAS data of 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.

Results: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) at C9orf72 on chromosome 9p21.2 (lowest p=2.6×10(-12) ) and one 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) ).

Interpretation: We identified common genetic variants at 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.
Original languageEnglish
Pages (from-to)120-133
Number of pages14
JournalAnnals of Neurology
Issue number1
Early online date16 Jun 2014
Publication statusPublished - Jul 2014


Dive into the research topics of 'C9orf72 and UNC13A are shared risk loci for ALS and FTD: A genome-wide meta-analysis'. Together they form a unique fingerprint.

Cite this