title: Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene.
abstract: BACKGROUND
  Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
  
  
  RESULTS
  We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).
  
  
  CONCLUSIONS
  Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
authors.forename: Marka
authors.initials: M
authors.lastname: van Blitterswijk
authors.forename: Bianca
authors.initials: B
authors.lastname: Mullen
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wojtas
authors.forename: Michael G
authors.initials: MG
authors.lastname: Heckman
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Diehl
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Baker
authors.forename: Mariely
authors.initials: M
authors.lastname: DeJesus-Hernandez
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Brown
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.forename: Ging-Yuek R
authors.initials: GY
authors.lastname: Hsiung
authors.forename: Heather
authors.initials: H
authors.lastname: Stewart
authors.forename: Anna M
authors.initials: AM
authors.lastname: Karydas
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Finger
authors.forename: Andrew
authors.initials: A
authors.lastname: Kertesz
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Sandra
authors.initials: S
authors.lastname: Weintraub
authors.forename: Marsel
authors.initials: M
authors.lastname: Mesulam
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.forename: Charles L
authors.initials: CL
authors.lastname: White
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Strong
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Carol
authors.initials: C
authors.lastname: Lippa
authors.forename: Richard
authors.initials: R
authors.lastname: Caselli
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.forename: Lea T
authors.initials: LT
authors.lastname: Grinberg
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Rademakers.Rosa@mayo.edu.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000401:mortality; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics* / Q000401:mortality; D010641:Phenotype; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins