Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia

International FTD- Genomics Consortium (BENUSSI L, BINETTI G, GHIDONI R autori Irccs)

Research output: Contribution to journalArticlepeer-review


Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ϵ2 and ϵ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
Original languageEnglish
Pages (from-to)1437-1446
Number of pages10
Issue number5
Publication statusPublished - 2017
Externally publishedYes


  • FTD
  • gene-based association study
  • GWAS
  • stress-signalling pathway
  • apolipoprotein E2
  • apolipoprotein E4
  • alpha 1 antitrypsin
  • apolipoprotein E
  • ARHGAP35 protein, human
  • carrier protein
  • guanine nucleotide exchange factor
  • repressor protein
  • SERPINA1 protein, human
  • TOMM40 protein, human
  • amygdala
  • anterior cingulate
  • Article
  • caudate nucleus
  • cerebellum
  • controlled study
  • frontal cortex
  • frontal variant frontotemporal dementia
  • frontotemporal dementia
  • gene expression profiling
  • gene locus
  • genetic association
  • genetic linkage
  • genetic risk
  • genome-wide association study
  • hemisphere
  • hippocampus
  • human
  • major clinical study
  • nucleus accumbens
  • priority journal
  • progressive nonfluent aphasia
  • putamen
  • semantic dementia
  • single nucleotide polymorphism
  • spinal cord
  • substantia nigra
  • allele
  • case control study
  • genetic association study
  • genetic predisposition
  • genetics
  • meta analysis
  • protection
  • risk factor
  • Alleles
  • alpha 1-Antitrypsin
  • Apolipoproteins E
  • Case-Control Studies
  • Frontotemporal Dementia
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Membrane Transport Proteins
  • Protective Factors
  • Repressor Proteins
  • Risk Factors


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