23 research outputs found
Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS
Protein network analysis reveals selectively vulnerable regions and biological processes in FTD
Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies
Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia
Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies
Background: Converging 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 findings: Using 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\u2014namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)\u2014and 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\u2013immune 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. Conclusions: We 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
CXCR4 involvement in neurodegenerative diseases
Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases
Recommended from our members
Beyond the Standard Model Physics at the HL-LHC and HE-LHC
This is the third out of five chapters of the final report [1] of the
Workshop on Physics at HL-LHC, and perspectives on HE-LHC [2]. It is devoted to
the study of the potential, in the search for Beyond the Standard Model (BSM)
physics, of the High Luminosity (HL) phase of the LHC, defined as
of data taken at a centre-of-mass energy of
, and of a possible future upgrade, the High Energy (HE) LHC,
defined as of data at a centre-of-mass energy of
. We consider a large variety of new physics models, both in a
simplified model fashion and in a more model-dependent one. A long list of
contributions from the theory and experimental (ATLAS, CMS, LHCb) communities
have been collected and merged together to give a complete, wide, and
consistent view of future prospects for BSM physics at the considered
colliders. On top of the usual standard candles, such as supersymmetric
simplified models and resonances, considered for the evaluation of future
collider potentials, this report contains results on dark matter and dark
sectors, long lived particles, leptoquarks, sterile neutrinos, axion-like
particles, heavy scalars, vector-like quarks, and more. Particular attention is
placed, especially in the study of the HL-LHC prospects, to the detector
upgrades, the assessment of the future systematic uncertainties, and new
experimental techniques. The general conclusion is that the HL-LHC, on top of
allowing to extend the present LHC mass and coupling reach by on most
new physics scenarios, will also be able to constrain, and potentially
discover, new physics that is presently unconstrained. Moreover, compared to
the HL-LHC, the reach in most observables will generally more than double at
the HE-LHC, which may represent a good candidate future facility for a final
test of TeV-scale new physics
Recommended from our members
Beyond the Standard Model Physics at the HL-LHC and HE-LHC
This is the third out of five chapters of the final report [1] of the
Workshop on Physics at HL-LHC, and perspectives on HE-LHC [2]. It is devoted to
the study of the potential, in the search for Beyond the Standard Model (BSM)
physics, of the High Luminosity (HL) phase of the LHC, defined as
of data taken at a centre-of-mass energy of
, and of a possible future upgrade, the High Energy (HE) LHC,
defined as of data at a centre-of-mass energy of
. We consider a large variety of new physics models, both in a
simplified model fashion and in a more model-dependent one. A long list of
contributions from the theory and experimental (ATLAS, CMS, LHCb) communities
have been collected and merged together to give a complete, wide, and
consistent view of future prospects for BSM physics at the considered
colliders. On top of the usual standard candles, such as supersymmetric
simplified models and resonances, considered for the evaluation of future
collider potentials, this report contains results on dark matter and dark
sectors, long lived particles, leptoquarks, sterile neutrinos, axion-like
particles, heavy scalars, vector-like quarks, and more. Particular attention is
placed, especially in the study of the HL-LHC prospects, to the detector
upgrades, the assessment of the future systematic uncertainties, and new
experimental techniques. The general conclusion is that the HL-LHC, on top of
allowing to extend the present LHC mass and coupling reach by on most
new physics scenarios, will also be able to constrain, and potentially
discover, new physics that is presently unconstrained. Moreover, compared to
the HL-LHC, the reach in most observables will generally more than double at
the HE-LHC, which may represent a good candidate future facility for a final
test of TeV-scale new physics