PMID- 29315334 OWN - NLM STAT- MEDLINE DCOM- 20181220 LR - 20231115 IS - 1549-1676 (Electronic) IS - 1549-1277 (Print) IS - 1549-1277 (Linking) VI - 15 IP - 1 DP - 2018 Jan TI - Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PG - e1002487 LID - 10.1371/journal.pmed.1002487 [doi] LID - e1002487 AB - 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. FAU - Broce, Iris AU - Broce I AUID- ORCID: 0000-0003-4932-1430 AD - Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, United States of America. FAU - Karch, Celeste M AU - Karch CM AUID- ORCID: 0000-0002-6854-5547 AD - Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America. FAU - Wen, Natalie AU - Wen N AD - Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America. FAU - Fan, Chun C AU - Fan CC AD - Department of Cognitive Sciences, University of California, San Diego, La Jolla, California, United States of America. FAU - Wang, Yunpeng AU - Wang Y AUID- ORCID: 0000-0001-9831-1090 AD - Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway. AD - Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. FAU - Tan, Chin Hong AU - Tan CH AUID- ORCID: 0000-0002-0980-9936 AD - Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, United States of America. FAU - Kouri, Naomi AU - Kouri N AUID- ORCID: 0000-0002-6841-9882 AD - Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America. FAU - Ross, Owen A AU - Ross OA AD - Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America. FAU - Hoglinger, Gunter U AU - Hoglinger GU AD - Department of Neurology, Technical University of Munich, Munich, Germany. AD - German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. AD - Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. FAU - Muller, Ulrich AU - Muller U AD - Institut for Humangenetik, Justus-Liebig-Universitat, Giessen, Germany. FAU - Hardy, John AU - Hardy J AD - Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom. CN - International FTD-Genomics Consortium FAU - Momeni, Parastoo AU - Momeni P AD - Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, United States of America. FAU - Hess, Christopher P AU - Hess CP AUID- ORCID: 0000-0002-5132-5302 AD - Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, United States of America. FAU - Dillon, William P AU - Dillon WP AD - Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, United States of America. FAU - Miller, Zachary A AU - Miller ZA AUID- ORCID: 0000-0002-5991-3053 AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Bonham, Luke W AU - Bonham LW AUID- ORCID: 0000-0002-2533-1266 AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Rabinovici, Gil D AU - Rabinovici GD AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Rosen, Howard J AU - Rosen HJ AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Schellenberg, Gerard D AU - Schellenberg GD AD - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. FAU - Franke, Andre AU - Franke A AD - Institute of Clinical Molecular Biology, Christian-Albrechts-Universitat zu Kiel, Kiel, Germany. FAU - Karlsen, Tom H AU - Karlsen TH AD - Norwegian PSC Research Center, Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway. AD - Division of Gastroenterology, Institute of Medicine, University of Bergen, Bergen, Norway. AD - K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway. FAU - Veldink, Jan H AU - Veldink JH AUID- ORCID: 0000-0001-5572-9657 AD - Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. FAU - Ferrari, Raffaele AU - Ferrari R AD - Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom. FAU - Yokoyama, Jennifer S AU - Yokoyama JS AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Miller, Bruce L AU - Miller BL AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Andreassen, Ole A AU - Andreassen OA AD - Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway. AD - Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. FAU - Dale, Anders M AU - Dale AM AUID- ORCID: 0000-0002-6126-2966 AD - Department of Cognitive Sciences, University of California, San Diego, La Jolla, California, United States of America. AD - Department of Radiology, University of California, San Diego, La Jolla, California, United States of America. AD - Department of Neurosciences, University of California, San Diego, La Jolla, California, United States of America. FAU - Desikan, Rahul S AU - Desikan RS AUID- ORCID: 0000-0002-4151-6017 AD - Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, United States of America. AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Sugrue, Leo P AU - Sugrue LP AUID- ORCID: 0000-0001-7315-4519 AD - Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, United States of America. LA - eng GR - MC_UU_00005/12/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00024/9/MRC_/Medical Research Council/United Kingdom GR - P01 AG017586/AG/NIA NIH HHS/United States GR - P01 AG026276/AG/NIA NIH HHS/United States GR - G0900652/MRC_/Medical Research Council/United Kingdom GR - K01 AG049152/AG/NIA NIH HHS/United States GR - MC_U123160651/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00024/1/MRC_/Medical Research Council/United Kingdom GR - U24 DA041123/DA/NIDA NIH HHS/United States GR - P01 AG003991/AG/NIA NIH HHS/United States GR - P50 AG005681/AG/NIA NIH HHS/United States GR - K01 AG046374/AG/NIA NIH HHS/United States GR - G1100540/MRC_/Medical Research Council/United Kingdom GR - MC_U105597119/MRC_/Medical Research Council/United Kingdom GR - G0400074/MRC_/Medical Research Council/United Kingdom GR - MC_U123160657/MRC_/Medical Research Council/United Kingdom GR - G0502157/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Meta-Analysis PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180109 PL - United States TA - PLoS Med JT - PLoS medicine JID - 101231360 SB - IM EIN - PLoS Med. 2018 Jan 29;15(1):e1002504. PMID: 29377952 MH - Aged MH - Frontotemporal Dementia/*genetics MH - Genetic Predisposition to Disease/*genetics MH - *Genome-Wide Association Study MH - Humans MH - Middle Aged MH - *Polymorphism, Single Nucleotide PMC - PMC5760014 COIS- I have read the journal's policy and the authors of this manuscript have the following competing interests: OAA reports patent pending for statistical genetics tool. OAA also received speakers's honorarium from Lundbeck. JHV's institute received consultancy fees from Vertex Pharmaceuticals. JH reports consulting for Cytox Genetics. AMD reports that he is a Founder of and holds equity in CorTechs Labs, Inc., and serves on its Scientific Advisory Board. AMD is a member of the Scientific Advisory Board of Human Longevity, Inc., and receives funding through research grants with General Electric Healthcare (the terms of these arrangements have been reviewed by and approved by the University of California, San Diego in accordance with its conflict of interest policies). AMD has a pending patent entitled "SYSTEMS AND METHODS FOR IDENTIFYING POLYMORPHISMS" through UC San Diego. GDR declared to receive research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare and Piramal. GDR also served on Scientific Advisory Boards for: Merck, Genentech, Roche. BM is a member of the Editorial Board of PLOS Medicine. FIR - Ferrari, Raffaele IR - Ferrari R FIR - Hernandez, Dena IR - Hernandez DG FIR - Nalls, Michael IR - Nalls MA FIR - Rohrer, Jonathan IR - Rohrer JD FIR - Ramasamy, Adaikalavan IR - Ramasamy A FIR - Kwok, John IR - Kwok JBJ FIR - Dobson-Stone, Carol IR - Dobson-Stone C FIR - Brooks, William IR - Brooks WS FIR - Schofield, Peter IR - Schofield PR FIR - Halliday, Glenda IR - Halliday GM FIR - Hodges, John IR - Hodges JR FIR - Piguet, Olivier IR - Piguet O FIR - Bartley, Lauren IR - Bartley L FIR - Thompson, Elizabeth IR - Thompson E FIR - Haan, Eric IR - Haan E FIR - Hernandez, Isabel IR - Hernandez I FIR - Ruiz, Agustin IR - Ruiz A FIR - Boada, Merce IR - Boada M FIR - Borroni, Barbara IR - Borroni B FIR - Padovani, Alessandro IR - Padovani A FIR - Cruchaga, Carlos IR - Cruchaga C FIR - Cairns, Nigel IR - Cairns NJ FIR - Benussi, Luisa IR - Benussi L FIR - Binetti, Giuliano IR - Binetti G FIR - Ghidoni, Roberta IR - Ghidoni R FIR - Forloni, Gianluigi IR - Forloni G FIR - Galimberti, Daniela IR - 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Hardy J FIR - Momeni, Parastoo IR - Momeni P EDAT- 2018/01/10 06:00 MHDA- 2018/12/21 06:00 PMCR- 2018/01/09 CRDT- 2018/01/10 06:00 PHST- 2017/07/03 00:00 [received] PHST- 2017/12/05 00:00 [accepted] PHST- 2018/01/10 06:00 [entrez] PHST- 2018/01/10 06:00 [pubmed] PHST- 2018/12/21 06:00 [medline] PHST- 2018/01/09 00:00 [pmc-release] AID - PMEDICINE-D-17-02291 [pii] AID - 10.1371/journal.pmed.1002487 [doi] PST - epublish SO - PLoS Med. 2018 Jan 9;15(1):e1002487. doi: 10.1371/journal.pmed.1002487. eCollection 2018 Jan.