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

Mishra, A; Ferrari, R; Heutink, P; Hardy, J; Pijnenburg, Y; Posthuma, D; (2017) Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia. Brain , 140 (5) pp. 1437-1446. 10.1093/brain/awx066. Green open access

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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.

Type: Article
Title: Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/awx066
Publisher version: http://doi.org/10.1093/brain/awx066
Language: English
Additional information: © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Keywords: Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences, Neurosciences & Neurology, gene-based association study, GWAS, FTD, MAGMA, stress-signalling pathway, GENOME-WIDE ASSOCIATION, CORTICOSTEROID-BINDING GLOBULIN, LOBAR DEGENERATION, ALZHEIMERS-DISEASE, DIAGNOSTIC-CRITERIA, PARKINSONS-DISEASE, BEHAVIORAL VARIANT, APOLIPOPROTEIN-E, NEURODEGENERATION, HERITABILITY
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1555358
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