title: C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis.
abstract: 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 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.
  
  
  RESULTS
  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) ).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Diekstra
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: John C
authors.initials: JC
authors.lastname: van Swieten
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Michael A
authors.initials: MA
authors.lastname: van Es
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.forename: Max
authors.initials: M
authors.lastname: Koppers
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Philip
authors.initials: P
authors.lastname: van Damme
authors.forename: Judith
authors.initials: J
authors.lastname: Melki
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.forename: Aleksey
authors.initials: A
authors.lastname: Shatunov
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.forename: Isabella
authors.initials: I
authors.lastname: Fogh
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: David
authors.initials: D
authors.lastname: Czell
authors.forename: Markus
authors.initials: M
authors.lastname: Weber
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D042622:DNA Repeat Expansion / Q000235:genetics; D057180:Frontotemporal Dementia / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods* / Q000639:trends; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D009419:Nerve Tissue Proteins; D011506:Proteins; C485548:UNC13B protein, human