Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Autor:	Broce, Iris, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Waldö ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsuing GYR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wasserman EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky E, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossmann M, Trojanowski JQ, van der Zee J, Deschamps W, Van Langenhove T, Cruts M, Van Broeckhoven C, Cappa SF, Le Ber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutnik P, Snowden J, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Peterson RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebert F, Kapogiannis D, Ferucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P.
Přispěvatelé:	Broce, Iris [0000-0003-4932-1430], Karch, Celeste M [0000-0002-6854-5547], Wang, Yunpeng [0000-0001-9831-1090], Tan, Chin Hong [0000-0002-0980-9936], Kouri, Naomi [0000-0002-6841-9882], Hess, Christopher P [0000-0002-5132-5302], Miller, Zachary A [0000-0002-5991-3053], Bonham, Luke W [0000-0002-2533-1266], Veldink, Jan H [0000-0001-5572-9657], Dale, Anders M [0000-0002-6126-2966], Desikan, Rahul S [0000-0002-4151-6017], Sugrue, Leo P [0000-0001-7315-4519], Apollo - University of Cambridge Repository, Neurology, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Divisions, Rademakers, Rosa, Int FTD-Genomics Consortium, Broce, Iri, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Brooks, W, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsuing, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wasserman, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, E, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossmann, M, Trojanowski, Jq, van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutnik, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Peterson, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Egp, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebert, F, Kapogiannis, D, Ferucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, Momeni, P.
Rok vydání:	2018
Předmět:	0301 basic medicine Linkage disequilibrium Gene Expression Genome-wide association study Neurodegenerative Medical and Health Sciences Motor Neuron Diseases 0302 clinical medicine Medicine and Health Sciences 2.1 Biological and endogenous factors Corticobasal degeneration genetics [Genetic Predisposition to Disease] genetics [Frontotemporal Dementia] Genetics Medicine (all) Neurodegenerative Diseases Single Nucleotide Genomics General Medicine Middle Aged Colitis LRRK2 3. Good health Neurology Manchester Institute for Collaborative Research on Ageing Frontotemporal Dementia Neurological Medicine Research Article Frontotemporal dementia ResearchInstitutes_Networks_Beacons/MICRA Immunology Rheumatoid Arthritis Single-nucleotide polymorphism Gastroenterology and Hepatology Human leukocyte antigen Biology Autoimmune Disease Polymorphism Single Nucleotide Autoimmune Diseases 03 medical and health sciences Rare Diseases Rheumatology Clinical Research General & Internal Medicine FTD GWA Mental Health and Psychiatry mental disorders Acquired Cognitive Impairment Genome-Wide Association Studies medicine Ulcerative Colitis Humans Inflammatory and Immune System Genetic Predisposition to Disease ddc:610 Polymorphism Aged Genetic association Genome-Wide Association Study International FTD-Genomics Consortium Prevention Arthritis Human Genome Inflammatory Bowel Disease Amyotrophic Lateral Sclerosis Neurosciences Correction Biology and Life Sciences Computational Biology nutritional and metabolic diseases Human Genetics Genome Analysis medicine.disease Brain Disorders nervous system diseases 030104 developmental biology Genetic Loci Genetics of Disease Dementia Clinical Immunology Human medicine Clinical Medicine Digestive Diseases 030217 neurology & neurosurgery
Zdroj:	Broce, I, Karch, C M, Wen, N, Fan, C C, Wang, Y, Hong Tan, C, Kouri, N, Ross, O A, Höglinger, G N U, Muller, U, Hardy, J, Momeni, P, Hess, C P, Dillon, W P, Miller, Z A, Bonham, L W, Rabinovici, G D, Rosen, H J, Schellenberg, G D, Franke, A, Karlsen, T H, Veldink, J H, Ferrari, R, Yokoyama, J S, Miller, B L, Andreassen, O A, Dale, A M, Desikan, R S, Sugrue, L P, Ferrari, R, Hernandez, D G, Nalls, M A, Rohrer, J D, Ramasamy, A, Kwok, J B J, Dobson-Stone, C, Brooks, W S, Schofield, P R, Halliday, G M, Hodges, J R, Fox, N C, Heutink, P, van Swieten, J C, Dopper, E G P, Pijnenburg, Y A L, Scheltens, P, van Swieten, J, Dopper, E, Pijnenburg, Y, Scheltens, P & International FTD-Genomics Consortium 2018, ' Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies ', PLoS Medicine, vol. 15, no. 1, e1002487 . https://doi.org/10.1371/journal.pmed.1002487 Broce, I, Karch, C M, Wen, N, Fan, C C, Wang, Y, Hong Tan, C, Kouri, N, Ross, O A, Höglinger, G U, Muller, U, Hardy, J, Momeni, P, Hess, C P, Dillon, W P, Miller, Z A, Bonham, L W, Rabinovici, G D, Rosen, H J, Schellenberg, G D, Franke, A, Karlsen, T H, Veldink, J H, Ferrari, R, Yokoyama, J S, Miller, B L, Andreassen, O A, Dale, A M, Desikan, R S, Sugrue, L P, Ferrari, R, Hernandez, D G, Nalls, M A, Rohrer, J D, Ramasamy, A, Kwok, J B J, Dobson-Stone, C, Brooks, W S, Schofield, P R, Halliday, G M, Hodges, J R, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Rowe, J B, Nielsen, J E, Hjermind, L E & International FTD-Genomics Consortium 2018, ' Immune-related genetic enrichment in frontotemporal dementia : An analysis of genome-wide association studies ', PLoS Medicine, vol. 15, no. 1, e1002487 . https://doi.org/10.1371/journal.pmed.1002487 PLoS Medicine, 15(1):e1002487. Public Library of Science International FTD-Genomics Consortium 2018, ' Immune-related genetic enrichment in frontotemporal dementia : An analysis of genome-wide association studies ', PLOS Medicine, vol. 15, no. 1, e1002487 . https://doi.org/10.1371/journal.pmed.1002487 PLoS Medicine, Vol 15, Iss 1, p e1002487 (2018) PLoS medicine PLoS medicine 15(1), e1002487 (2018). doi:10.1371/journal.pmed.1002487 PLoS Medicine PLoS medicine, vol 15, iss 1
ISSN:	1549-1676 1549-1277
Popis:	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. Rahul Desikan and colleagues use summary data from genome-wide association studies to investigate genetic overlap between frontotemporal dementia and a several immune-mediated diseases, and identify microglia and inflammation-associated genes that may play a role in FTD pathogenesis. Author summary Why was this study done? Frontotemporal dementia (FTD) is the leading cause of dementia in individuals less than 65 years old. Currently, there is no approved treatment of FTD and no diagnostic tests for predicting disease onset or measuring progression. Increasing evidence suggests that inflammation and immune system dysfunction play an important role in the pathogenesis of FTD. What did the researchers do and find? We used summary data from genome-wide association studies to investigate genetic overlap, or “pleiotropy,” between FTD and a variety of immune-mediated diseases. Through this approach, we found extensive FTD–immune genetic overlap within the HLA region on Chromosome 6, an area rich in genes related to microglial function, as well as in 3 genes not previously identified as contributing to the pathophysiology of FTD. Pointing to the functional relevance of these genetic results, we found that these candidate FTD–immune genes are differentially expressed in postmortem brains from patients with FTD compared to controls, and in microglia/macrophages compared with other central nervous system cells. Using bioinformatics tools, we explored protein and genetic interactions among our candidate FTD–immune genes. These results suggest that rather than a few individual loci, large portions of the HLA region may be associated with increased FTD risk. What do these findings mean? Immune dysfunction may play a role in the pathophysiology of a subset of FTD cases. For a subset of patients in whom immune dysfunction in general—and microglial activation in particular—is central to disease pathophysiology, anti-inflammatory treatment is an important area for further investigation.
Databáze:	OpenAIRE
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