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https://hdl.handle.net/2440/95680
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Type: | Journal article |
Title: | Frontotemporal dementia and its subtypes: a genome-wide association study |
Author: | Ferrari, R. Hernandez, D. Nalls, M. Rohrer, J. Ramasamy, A. Kwok, J. Dobson-Stone, C. Brooks, W. Schofield, P. Halliday, G. Hodges, J. Piguet, O. Bartley, L. Thompson, E. Haan, E. Hernández, I. Ruiz, A. Boada, M. Borroni, B. Padovani, A. et al. |
Citation: | Lancet Neurology, 2014; 13(7):686-699 |
Publisher: | Elsevier |
Issue Date: | 2014 |
ISSN: | 1474-4422 1474-4465 |
Statement of Responsibility: | Raffaele Ferrari ... Eric Hann ... et al. |
Abstract: | BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms. FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. INTERPRETATION: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. FUNDING: The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center. |
Keywords: | Genotype Frontotemporal Dementia |
Rights: | © 2014 Elsevier Ltd. All rights reserved. |
DOI: | 10.1016/S1474-4422(14)70065-1 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/510217 http://purl.org/au-research/grants/nhmrc/1005769 http://purl.org/au-research/grants/nhmrc/510217 http://purl.org/au-research/grants/nhmrc/1005769 http://purl.org/au-research/grants/nhmrc/630428 http://purl.org/au-research/grants/nhmrc/401184 http://purl.org/au-research/grants/nhmrc/630434 http://purl.org/au-research/grants/nhmrc/1029538 http://purl.org/au-research/grants/nhmrc/1037746 http://purl.org/au-research/grants/nhmrc/1029538 http://purl.org/au-research/grants/nhmrc/1037746 http://purl.org/au-research/grants/nhmrc/1022684 http://purl.org/au-research/grants/nhmrc/1003139 G0901254 G0802462 P30-NS069329-01 AG032953 AG017586 AG010124 NS044266 Prin 2010-prot.2010PWNJXK P50 AG016574 R01 NS080882 R01 NS065782 P50 NS72187 P50NS072187 P50AG016574 R01 AG037491 AG032306 |
Published version: | http://dx.doi.org/10.1016/s1474-4422(14)70065-1 |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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