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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

Published on Jun 1, 2019in Acta Neuropathologica 18.17
· DOI :10.1007/s00401-019-01962-9
Cyril Pottier15
Estimated H-index: 15
(Mayo Clinic),
Yingxue Ren2
Estimated H-index: 2
(Mayo Clinic)
+ 102 AuthorsRosa Rademakers76
Estimated H-index: 76
(Mayo Clinic)
Cite
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.
  • References (103)
  • Citations (4)
Cite
References103
Newest
Published on Jun 1, 2019in Acta Neuropathologica 18.17
Rita Cacace4
Estimated H-index: 4
(University of Antwerp),
Bavo Heeman5
Estimated H-index: 5
(University of Antwerp)
+ 26 AuthorsMojca Strazisar7
Estimated H-index: 7
(University of Antwerp)
Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disea...
Published on Apr 1, 2019in Neuropathology and Applied Neurobiology 6.88
Daniel T. Ohm1
Estimated H-index: 1
(NU: Northwestern University),
Garam Kim3
Estimated H-index: 3
(NU: Northwestern University)
+ 6 AuthorsChangiz Geula49
Estimated H-index: 49
(NU: Northwestern University)
Published on Jan 1, 2019in Acta Neuropathologica 18.17
Ethan G. Geier13
Estimated H-index: 13
(UCSF: University of California, San Francisco),
Mathieu Bourdenx2
Estimated H-index: 2
(Albert Einstein College of Medicine)
+ 22 AuthorsAntonio Diaz4
Estimated H-index: 4
(Albert Einstein College of Medicine)
Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case–control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3541), and found suggestive evidence that gene-wide aggregate rare variant...
Published on Jan 1, 2019in Neurobiology of Aging 4.40
Katerina Placek2
Estimated H-index: 2
(UPenn: University of Pennsylvania),
G. Michael Baer2
Estimated H-index: 2
(UPenn: University of Pennsylvania)
+ 10 AuthorsVivianna M. Van Deerlin65
Estimated H-index: 65
(UPenn: University of Pennsylvania)
Abstract The majority (90%–95%) of amyotrophic lateral sclerosis (ALS) is sporadic, and ∼50% of patients develop symptoms of frontotemporal degeneration (FTD) associated with shorter survival. The genetic polymorphism rs12608932 in UNC13A confers increased risk of sporadic ALS and sporadic FTD and modifies survival in ALS. Here, we evaluate whether rs12608932 is also associated with frontotemporal disease in sporadic ALS. We identified reduced cortical thickness in sporadic ALS with T1-weighted ...
Published on Nov 1, 2018in Neurobiology of Aging 4.40
Martina de Majo4
Estimated H-index: 4
('KCL': King's College London),
Simon Topp19
Estimated H-index: 19
('KCL': King's College London)
+ 30 AuthorsFrank Baas63
Estimated H-index: 63
(LUMC: Leiden University Medical Center)
Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized a subset of these: p.G217R, p.R357X, and p.C471Y. Here, we show that the p...
Published on Sep 1, 2018in Nature Reviews Neurology 21.16
Rubika Balendra1
Estimated H-index: 1
(UCL Institute of Neurology),
Aaron Isaacs62
Estimated H-index: 62
(UCL Institute of Neurology)
The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat ...
Published on Jun 28, 2018in European Journal of Human Genetics 3.65
W. van Rheenen4
Estimated H-index: 4
,
Sara L. Pulit21
Estimated H-index: 21
+ 35 AuthorsLeonard H. van den Berg84
Estimated H-index: 84
The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn fro...
Published on May 9, 2018in Journal of Virology 4.32
Binbin Xue7
Estimated H-index: 7
,
Huiyi Li1
Estimated H-index: 1
+ 6 AuthorsHaizhen Zhu15
Estimated H-index: 15
Published on Mar 1, 2018in Neuron 14.40
Aude Nicolas10
Estimated H-index: 10
(NIH: National Institutes of Health),
Kevin Kenna16
Estimated H-index: 16
(UMMS: University of Massachusetts Medical School)
+ 200 AuthorsPamela Keagle13
Estimated H-index: 13
(UMMS: University of Massachusetts Medical School)
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causat...
Cited By4
Newest
Published on Jul 19, 2019in Nature Reviews Neurology 21.16
Fiona M. Bright (USYD: University of Sydney), Eryn L. Werry9
Estimated H-index: 9
(USYD: University of Sydney)
+ 8 AuthorsMichael Kassiou39
Estimated H-index: 39
(USYD: University of Sydney)
Frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders with different pathological signatures, genetic variability and complex disease mechanisms, for which no effective treatments exist. Despite advances in understanding the underlying pathology of FTD, sensitive and specific fluid biomarkers for this disease are lacking. As in other types of dementia, mounting evidence suggests that neuroinflammation is involved in the progression of FTD, including cortical ...
Published on Jul 2, 2019in bioRxiv
Serge Nataf19
Estimated H-index: 19
(University of Lyon),
Marine Guillen (University of Lyon), Laurent Pays9
Estimated H-index: 9
(University of Lyon)
There is circumstantial evidence that, under neurodegenerative conditions, peptides deriving from aggregated or misfolded brain proteins elicit adaptive immune responses. On another hand, several genes involved in familial forms of neurodegenerative diseases were found to exert key innate immune functions. However, whether or not such observations are causally linked remains unknown. To start addressing this issue, we followed a systems biology strategy based on the mining of large proteomics, g...
Published on Jun 1, 2019in Acta Neuropathologica 18.17
Rita Cacace4
Estimated H-index: 4
(University of Antwerp),
Bavo Heeman5
Estimated H-index: 5
(University of Antwerp)
+ 26 AuthorsMojca Strazisar7
Estimated H-index: 7
(University of Antwerp)
Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disea...
Published on May 1, 2019in Nature Reviews Neurology 21.16
Daniela Galimberti54
Estimated H-index: 54
(University of Milan)
A new study has identified novel genes involved in sporadic frontotemporal lobar degeneration with neuronal inclusions of TAR DNA-binding protein 43. These findings might enable the elucidation of pathogenic mechanisms of the disease and have implications for the identification of potential therapeutic targets.
Published on Apr 1, 2019in Immunity 21.52
Timothy G. Hammond39
Estimated H-index: 39
(Broad Institute),
Samuel E. Marsh7
Estimated H-index: 7
(Broad Institute),
Beth Stevens38
Estimated H-index: 38
Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and ...
Published in bioRxiv
J. Nicholas Cochran6
Estimated H-index: 6
,
Emily McKinley (UAB: University of Alabama at Birmingham)+ -3 AuthorsEthan G. Geier13
Estimated H-index: 13
(UCSF: University of California, San Francisco)
We assessed the utility of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with C9orf72 repeat expansion testing. All returned sequencing results were Sanger validated clinically. Prior clinical diagnoses included Alzheimer9s disease, frontotemporal dementia, and unspecified dementia. The mean age-of-onset was 54 (41-76). 50% of patients had a strong family history, 37.5% had some, and 12.5% had no known...