title: Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia.
abstract: 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 ɛ2 and ɛ4 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.
authors.affiliation: Department of Complex Trait Genetics, VU University, Center for Neurogenomics and Cognitive Research, Amsterdam, 1081 HV, The Netherlands.
authors.forename: Aniket
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Department of Molecular Neuroscience, UCL, Russell Square House, 9-12 Russell Square House London, WC1B 5EH, UK.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.|German Center for Neurodegenerative Diseases (DZNE)-Tübingen, 72076, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.affiliation: Department of Molecular Neuroscience, UCL, Russell Square House, 9-12 Russell Square House London, WC1B 5EH, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Alzheimer Center and Department of Neurology, VU University Medical Center (VUMC), Neuroscience Campus Amsterdam, Amsterdam, 1081 HV, The Netherlands.
authors.forename: Yolande
authors.initials: Y
authors.lastname: Pijnenburg
authors.affiliation: Department of Complex Trait Genetics, VU University, Center for Neurogenomics and Cognitive Research, Amsterdam, 1081 HV, The Netherlands.|Department of Clinical Genetics, VU University Medical Center (VUMC), Neuroscience Campus Amsterdam, Amsterdam, 1081 HV, The Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Posthuma
mesh_terms: D000483:Alleles; D001057:Apolipoproteins E / Q000235:genetics*; D016022:Case-Control Studies; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D065840:Protective Factors; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: C074560:ARHGAP35 protein, human; D001057:Apolipoproteins E; D020662:Guanine Nucleotide Exchange Factors; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D012097:Repressor Proteins; C043392:SERPINA1 protein, human; C400783:TOMM40 protein, human; D000515:alpha 1-Antitrypsin
keywords: FTD; GWAS; MAGMA; gene-based association study; stress-signalling pathway