Dataset Information

Frontotemporal dementia and its subtypes: a genome-wide association study.

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.

SUBMITTER: Ferrari R

PROVIDER: S-EPMC4112126 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Frontotemporal dementia and its subtypes: a genome-wide association study.

Ferrari Raffaele R Hernandez Dena G DG Nalls Michael A MA Rohrer Jonathan D JD Ramasamy Adaikalavan A Kwok John B J JB Dobson-Stone Carol C Brooks William S WS Schofield Peter R PR Halliday Glenda M GM Hodges John R JR Piguet Olivier O Bartley Lauren L Thompson Elizabeth E Haan Eric E Hernández Isabel I Ruiz Agustín A Boada Mercè M Borroni Barbara B Padovani Alessandro A Cruchaga Carlos C Cairns Nigel J NJ Benussi Luisa L Binetti Giuliano G Ghidoni Roberta R Forloni Gianluigi G Galimberti Daniela D Fenoglio Chiara C Serpente Maria M Scarpini Elio E Clarimón Jordi J Lleó Alberto A Blesa Rafael R Waldö Maria Landqvist ML Nilsson Karin K Nilsson Christer C Mackenzie Ian R A IR Hsiung Ging-Yuek R GY Mann David M A DM Grafman Jordan J Morris Christopher M CM Attems Johannes J Griffiths Timothy D TD McKeith Ian G IG Thomas Alan J AJ Pietrini P P Huey Edward D ED Wassermann Eric M EM Baborie Atik A Jaros Evelyn E Tierney Michael C MC Pastor Pau P Razquin Cristina C Ortega-Cubero Sara S Alonso Elena E Perneczky Robert R Diehl-Schmid Janine J Alexopoulos Panagiotis P Kurz Alexander A Rainero Innocenzo I Rubino Elisa E Pinessi Lorenzo L Rogaeva Ekaterina E St George-Hyslop Peter P Rossi Giacomina G Tagliavini Fabrizio F Giaccone Giorgio G Rowe James B JB Schlachetzki Johannes C M JC Uphill James J Collinge John J Mead Simon S Danek Adrian A Van Deerlin Vivianna M VM Grossman Murray M Trojanowski John Q JQ van der Zee Julie J Deschamps William W Van Langenhove Tim T Cruts Marc M Van Broeckhoven Christine C Cappa Stefano F SF Le Ber Isabelle I Hannequin Didier D Golfier Véronique V Vercelletto Martine M Brice Alexis A Nacmias Benedetta B Sorbi Sandro S Bagnoli Silvia S Piaceri Irene I Nielsen Jørgen E JE Hjermind Lena E LE Riemenschneider Matthias M Mayhaus Manuel M Ibach Bernd B Gasparoni Gilles G Pichler Sabrina S Gu Wei W Rossor Martin N MN Fox Nick C NC Warren Jason D JD Spillantini Maria Grazia MG Morris Huw R HR Rizzu Patrizia P Heutink Peter P Snowden Julie S JS Rollinson Sara S Richardson Anna A Gerhard Alexander A Bruni Amalia C AC Maletta Raffaele R Frangipane Francesca F Cupidi Chiara C Bernardi Livia L Anfossi Maria M Gallo Maura M Conidi Maria Elena ME Smirne Nicoletta N Rademakers Rosa R Baker Matt M Dickson Dennis W DW Graff-Radford Neill R NR Petersen Ronald C RC Knopman David D Josephs Keith A KA Boeve Bradley F BF Parisi Joseph E JE Seeley William W WW Miller Bruce L BL Karydas Anna M AM Rosen Howard H van Swieten John C JC Dopper Elise G P EG Seelaar Harro H Pijnenburg Yolande A L YA Scheltens Philip P Logroscino Giancarlo G Capozzo Rosa R Novelli Valeria V Puca Annibale A AA Franceschi Massimo M Postiglione Alfredo A Milan Graziella G Sorrentino Paolo P Kristiansen Mark M Chiang Huei-Hsin HH Graff Caroline C Pasquier Florence F Rollin Adeline A Deramecourt Vincent V Lebert Florence F Kapogiannis Dimitrios D Ferrucci Luigi L Pickering-Brown Stuart S Singleton Andrew B AB Hardy John J Momeni Parastoo P

The Lancet. Neurology 20140701 7

<h4>Background</h4>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.<h4>Methods</h4>We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy control ...[more]

PMID: 24943344

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Project description:BackgroundConverging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.Methods and findingsUsing large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal.ConclusionsWe show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

Project description:IMPORTANCE:Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. OBJECTIVE:To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. DESIGN, SETTING, AND PARTICIPANTS:We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer's Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. MAIN OUTCOMES AND MEASURES:Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. RESULTS:Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. CONCLUSIONS AND RELEVANCE:Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.

Project description:Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants. To identify rare and new common variant FTD risk loci and provide more insight into the heritability of C9ORF72-related FTD, we performed a GWAS consisting of 354 FTD patients (including and excluding N = 28 pathological repeat carriers) and 4209 control subjects. The Haplotype Reference Consortium was used as reference panel, allowing for the imputation of rare genetic variants. Two rare genetic variants nearby C9ORF72 were strongly associated with FTD in the discovery (rs147211831: OR = 4.8, P = 9.2 × 10-9, rs117204439: OR = 4.9, P = 6.0 × 10-9) and replication analysis (P < 1.1 × 10-3). These variants also significantly associated with amyotrophic lateral sclerosis in a publicly available dataset. Using haplotype analyses in 1200 individuals, we showed that these variants tag a sub-haplotype of the founder haplotype of the repeat expansion that was previously found to be present in virtually all pathological C9ORF72 G4C2 repeat lengths. This new risk haplotype was 10 times more likely to contain a C9ORF72 pathological repeat length compared to founder haplotypes without one of the two risk variants (~22% versus ~2%; P = 7.70 × 10-58). In haplotypes without a pathologic expansion, the founder risk haplotype had a higher number of repeats (median = 12 repeats) compared to the founder haplotype without the risk variants (median = 8 repeats) (P = 2.05 × 10-260). In conclusion, the identified risk haplotype, which is carried by ~4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 G4C2. These findings strongly indicate that longer C9ORF72 repeats are unstable and more likely to convert to germline pathological C9ORF72 repeat expansions.

Dataset Information

Frontotemporal dementia and its subtypes: a genome-wide association study.

Publications

Frontotemporal dementia and its subtypes: a genome-wide association study.

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