Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies
Por:
Broce, I, Karch, CM, Wen, N, Fan, CC, Wang, YP, Tan, CH, Kouri, N, Ross, OA, Hoglinger, GU, Muller, U, Hardy, J, Momeni, P, Hess, CP, Dillon, WP, Miller, ZA, Bonham, LW, Rabinovici, GD, Rosen, HJ, Schellenberg, GD, Franke, A, Karlsen, TH, Veldink, JH, Ferrari, R, Yokoyama, JS, Miller, BL, Andreassen, OA, Dale, AM, Desikan, RS, Sugrue, LP, Clarimón J., Lleó A., Blesa R., Hardy, John
Publicada:
1 ene 2018
Resumen:
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-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.
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.
Filiaciones:
Broce, I:
Univ Calif San Francisco, Neuroradiol Sect, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA
Karch, CM:
Washington Univ, Dept Psychiat, St Louis, MO USA
Wen, N:
Washington Univ, Dept Psychiat, St Louis, MO USA
Fan, CC:
Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA
Wang, YP:
Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway
Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway
Tan, CH:
Univ Calif San Francisco, Neuroradiol Sect, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA
Kouri, N:
Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA
Ross, OA:
Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA
Hoglinger, GU:
Tech Univ Munich, Dept Neurol, Munich, Germany
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
Muller, U:
Justus Liebig Univ, Inst Humangenet, Giessen, Germany
Hardy, J:
UCL, Inst Neurol, Dept Mol Neurosci, London, England
Momeni, P:
Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Lab Neurogenet, Lubbock, TX 79430 USA
Hess, CP:
Univ Calif San Francisco, Neuroradiol Sect, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA
Dillon, WP:
Univ Calif San Francisco, Neuroradiol Sect, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA
Miller, ZA:
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
Bonham, LW:
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
Rabinovici, GD:
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
Rosen, HJ:
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
Schellenberg, GD:
Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA
Franke, A:
Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Karlsen, TH:
Oslo Univ Hosp, Rikshosp, Norwegian PSC Res Ctr, Res Inst Internal Med,Div Canc Med Surg & Transpl, Oslo, Norway
Univ Bergen, Inst Med, Div Gastroenterol, Bergen, Norway
Oslo Univ Hosp, Rikshosp, KG Jebsen Inflammat Res Ctr, Res Inst Internal Med,Div Canc Med Surg & Transpl, Oslo, Norway
Veldink, JH:
Univ Med Ctr Utrecht, Dept Neurol, Brain Ctr Rudolf Magnus, Utrecht, Netherlands
Ferrari, R:
UCL, Inst Neurol, Dept Mol Neurosci, London, England
Yokoyama, JS:
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
Miller, BL:
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
Andreassen, OA:
Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway
Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway
Dale, AM:
Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA
Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA
Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
Desikan, RS:
Univ Calif San Francisco, Neuroradiol Sect, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
Sugrue, LP:
Univ Calif San Francisco, Neuroradiol Sect, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA
Clarimón J.:
Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Lleó A.:
Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Blesa R.:
Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Hardy, John:
UCL, Inst Neurol, Dept Mol Neurosci, London, England
Green Submitted, Green Published, Green Accepted, gold
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