title: Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms.
abstract: Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.
authors: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway; Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, United States of America.
authors: Ole A
authors: OA
authors: Andreassen
authors: Multimodal Imaging Laboratory, University of California San Diego, La Jolla, CA 92093, United States of America; Department of Radiology, University of California San Diego, La Jolla, CA 92093, United States of America.
authors: Rahul S
authors: RS
authors: Desikan
authors: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway; Multimodal Imaging Laboratory, University of California San Diego, La Jolla, CA 92093, United States of America; Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.
authors: Yunpeng
authors: Y
authors: Wang
authors: Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, United States of America.
authors: Wesley K
authors: WK
authors: Thompson
authors: Multimodal Imaging Laboratory, University of California San Diego, La Jolla, CA 92093, United States of America; Cognitive Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, United States of America; Center for Human Development, University of California San Diego, La Jolla, CA 92093, United States of America.
authors: Andrew J
authors: AJ
authors: Schork
authors: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway; Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, 0407 Oslo, Norway.
authors: Verena
authors: V
authors: Zuber
authors: Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
authors: Nadezhda T
authors: NT
authors: Doncheva
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
authors: Eva
authors: E
authors: Ellinghaus
authors: Max Planck Institute for Informatics, 66123 Saarbrücken, Germany; Department of Bioinformatics, Institute of Biometrics and Medical Informatics, University Medicine Greifswald, 17475 Greifswald, Germany; Institute for Knowledge Discovery, Graz University of Technology, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
authors: Mario
authors: M
authors: Albrecht
authors: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway; Sørlandet Hospital, 3000 Kristiansand, Norway.
authors: Morten
authors: M
authors: Mattingsdal
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
authors: Andre
authors: A
authors: Franke
authors: BioTechMed-Graz, 8010 Graz, Austria.
authors: Benedicte A
authors: BA
authors: Lie
authors: Ian G
authors: IG
authors: Mills
authors: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, 0407 Oslo, Norway; Department of Cancer Prevention, Institute of Cancer Research and Department of Urology, Oslo University Hospital, 0407 Oslo, Norway.
authors: Ian
authors: I
authors: Mills
authors: Department of Medical Genetics, University of Oslo and Oslo University Hospital, 0407 Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, 0407 Oslo Norway.
authors: Pål
authors: P
authors: Aukrust
authors: Multimodal Imaging Laboratory, University of California San Diego, La Jolla, CA 92093, United States of America; Department of Radiology, University of California San Diego, La Jolla, CA 92093, United States of America.
authors: Linda K
authors: LK
authors: McEvoy
authors: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway; Department of Medical Genetics, University of Oslo and Oslo University Hospital, 0407 Oslo, Norway.
authors: Srdjan
authors: S
authors: Djurovic
authors: K.G.Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, 0407 Oslo, Norway; Division of Gastroenterology, Institute of Medicine, University of Bergen, 5000 Bergen, Norway; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, 0407 Oslo, Norway.
authors: Tom H
authors: TH
authors: Karlsen
authors: Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, United States of America; Multimodal Imaging Laboratory, University of California San Diego, La Jolla, CA 92093, United States of America; Department of Radiology, University of California San Diego, La Jolla, CA 92093, United States of America; Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.
authors: Anders M
authors: AM
authors: Dale
mesh_terms: D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics*; D056426:Genetic Loci; D058685:Genetic Pleiotropy; D055106:Genome-Wide Association Study; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000235:genetics; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood*
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D014280:Triglycerides