Dataset Information

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

ABSTRACT: Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value?=?4.82e - 08, OR?=?2.12), and two known loci: UNC13A, led by rs1297319 (p value?=?1.27e - 08, OR?=?1.50) and HLA-DQA2 led by rs17219281 (p value?=?3.22e - 08, OR?=?1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n???3) as compared to controls (n?=?0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

SUBMITTER: Pottier C

PROVIDER: S-EPMC6533145 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Pottier Cyril C Ren Yingxue Y Perkerson Ralph B RB Baker Matt M Jenkins Gregory D GD van Blitterswijk Marka M DeJesus-Hernandez Mariely M van Rooij Jeroen G J JGJ Murray Melissa E ME Christopher Elizabeth E McDonnell Shannon K SK Fogarty Zachary Z Batzler Anthony A Tian Shulan S Vicente Cristina T CT Matchett Billie B Karydas Anna M AM Hsiung Ging-Yuek Robin GR Seelaar Harro H Mol Merel O MO Finger Elizabeth C EC Graff Caroline C Öijerstedt Linn L Neumann Manuela M Heutink Peter P Synofzik Matthis M Wilke Carlo C Prudlo Johannes J Rizzu Patrizia P Simon-Sanchez Javier J Edbauer Dieter D Roeber Sigrun S Diehl-Schmid Janine J Evers Bret M BM King Andrew A Mesulam M Marsel MM Weintraub Sandra S Geula Changiz C Bieniek Kevin F KF Petrucelli Leonard L Ahern Geoffrey L GL Reiman Eric M EM Woodruff Bryan K BK Caselli Richard J RJ Huey Edward D ED Farlow Martin R MR Grafman Jordan J Mead Simon S Grinberg Lea T LT Spina Salvatore S Grossman Murray M Irwin David J DJ Lee Edward B EB Suh EunRan E Snowden Julie J Mann David D Ertekin-Taner Nilufer N Uitti Ryan J RJ Wszolek Zbigniew K ZK Josephs Keith A KA Parisi Joseph E JE Knopman David S DS Petersen Ronald C RC Hodges John R JR Piguet Olivier O Geier Ethan G EG Yokoyama Jennifer S JS Rissman Robert A RA Rogaeva Ekaterina E Keith Julia J Zinman Lorne L Tartaglia Maria Carmela MC Cairns Nigel J NJ Cruchaga Carlos C Ghetti Bernardino B Kofler Julia J Lopez Oscar L OL Beach Thomas G TG Arzberger Thomas T Herms Jochen J Honig Lawrence S LS Vonsattel Jean Paul JP Halliday Glenda M GM Kwok John B JB White Charles L CL Gearing Marla M Glass Jonathan J Rollinson Sara S Pickering-Brown Stuart S Rohrer Jonathan D JD Trojanowski John Q JQ Van Deerlin Vivianna V Bigio Eileen H EH Troakes Claire C Al-Sarraj Safa S Asmann Yan Y Miller Bruce L BL Graff-Radford Neill R NR Boeve Bradley F BF Seeley William W WW Mackenzie Ian R A IRA van Swieten John C JC Dickson Dennis W DW Biernacka Joanna M JM Rademakers Rosa R

Acta neuropathologica 20190209 6

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and ...[more]

PMID: 30739198

Similar Datasets

Project description:TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0-VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with "typical" TDP-43 immunoreactive inclusions (TDP type-α), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-β). We compared pathological, genetic (APOE4, TMEM106B and GRN variants), neuroimaging and clinical data between types, as well as compared neuroimaging between types and a group of TDP-43 negative cases (n = 309). Two-hundred forty-one cases were classified as TDP type-α (n = 131, 54%) or TDP type-β (n = 110, 46%). Type-α cases were older than type-β at death (median 89 years vs. 87 years; p = 0.02). Hippocampal sclerosis was present in 78 (60%) type-α cases and 16 (15%) type-β cases (p < 0.001). Type-α cases showed a pattern of widespread TDP-43 deposition commonly extending into temporal, frontal and brainstem regions (84% TDP-43 stage 4-6) while in type-β cases deposition was predominantly limbic, located in amygdala, entorhinal cortex and subiculum of the hippocampus (84% TDP-43 stages 1-3) (p < 0.001). There was a difference in the frequency of TMEM106B protective (GG) and risk (CC) haplotypes (SNP rs3173615 encoding p.T185S) in type-α cases compared to type-β cases (GG/CG/CC: 8%/42%/50% vs. 24%/49%/27%; p = 0.01). Type-α cases had smaller amygdala (- 10.6% [- 17.6%, - 3.5%]; p = 0.003) and hippocampal (- 14.4% [- 21.6%, - 7.3%]; p < 0.001) volumes on MRI at death compared to type-β cases, although both types had smaller amygdala and hippocampal volumes compared to TDP-43 negative cases (- 7.77%, - 21.6%; p < 0.001). These findings demonstrate that there is distinct heterogeneity of TDP-43 deposition in non-FTLD brains.

Dataset Information

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Publications

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets