title: Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease.
abstract: BACKGROUND
  Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis.
  
  
  RESULTS
  Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05-1.11; P=2.86×10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38×10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains.
  
  
  CONCLUSIONS
  We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.
authors: Department of Radiology, University of California, San Diego, La Jolla, CA.
authors: Rahul S
authors: RS
authors: Desikan
authors: Department of Cognitive Science, University of California, San Diego, La Jolla, CA.
authors: Andrew J
authors: AJ
authors: Schork
authors: Department of Neurosciences, University of California, San Diego, La Jolla, CA.|NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors: Yunpeng
authors: Y
authors: Wang
authors: Department of Psychiatry, University of California, San Diego, La Jolla, CA.
authors: Wesley K
authors: WK
authors: Thompson
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.
authors: Abbas
authors: A
authors: Dehghan
authors: Center for Cardiovascular Disease Prevention, Division of Preventative Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA.
authors: Paul M
authors: PM
authors: Ridker
authors: Center for Cardiovascular Disease Prevention, Division of Preventative Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA.
authors: Daniel I
authors: DI
authors: Chasman
authors: Department of Radiology, University of California, San Diego, La Jolla, CA.
authors: Linda K
authors: LK
authors: McEvoy
authors: Department of Neurosciences, University of California, San Diego, La Jolla, CA.
authors: Dominic
authors: D
authors: Holland
authors: Department of Radiology, University of California, San Diego, La Jolla, CA.|NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors: Chi-Hua
authors: CH
authors: Chen
authors: Department of Radiology, University of California, San Diego, La Jolla, CA.
authors: David S
authors: DS
authors: Karow
authors: Department of Radiology, University of California, San Diego, La Jolla, CA.|Department of Neurosciences, University of California, San Diego, La Jolla, CA.
authors: James B
authors: JB
authors: Brewer
authors: Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA.
authors: Christopher P
authors: CP
authors: Hess
authors: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Wales, United Kingdom.
authors: Julie
authors: J
authors: Williams
authors: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Wales, United Kingdom.
authors: Rebecca
authors: R
authors: Sims
authors: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Wales, United Kingdom.
authors: Michael C
authors: MC
authors: O'Donovan
authors: Department of Biostatistics, School of Public Health, Boston University, Boston, MA.
authors: Seung Hoan
authors: SH
authors: Choi
authors: Deparment of Internal Medicine, University of Washington, Seattle, WA.
authors: Joshua C
authors: JC
authors: Bis
authors: Deparment of Epidemiology, Erasmus MC, Rotterdam, Netherlands.|Departments of Radiology, Erasmus MC, Rotterdam, Netherlands.
authors: M Arfan
authors: MA
authors: Ikram
authors: Icelandic Heart Association, Kopavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Vilmundur
authors: V
authors: Gudnason
authors: Department of Biostatistics, School of Public Health, Boston University, Boston, MA.|The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA.
authors: Anita L
authors: AL
authors: DeStefano
authors: Deparment of Epidemiology, Erasmus MC, Rotterdam, Netherlands.
authors: Sven J
authors: SJ
authors: van der Lee
authors: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA; Group Health Research Institute, Group Health Cooperative, Seattle, WA.
authors: Bruce M
authors: BM
authors: Psaty
authors: Deparment of Epidemiology, Erasmus MC, Rotterdam, Netherlands.
authors: Cornelia M
authors: CM
authors: van Duijn
authors: Laboratory of Epidemiology, Demography and Biometry, Intramural Research Program, National Institute on Aging, Washington, DC.
authors: Lenore
authors: L
authors: Launer
authors: The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA.|Department of Neurology, Boston University School of Medicine, Boston, MA.
authors: Sudha
authors: S
authors: Seshadri
authors: The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL.
authors: Margaret A
authors: MA
authors: Pericak-Vance
authors: Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, NY.
authors: Richard
authors: R
authors: Mayeux
authors: Department of Epidemiology and Biostatistics and Institute for Computational Biology, Case Western University, Cleveland, OH.
authors: Jonathan L
authors: JL
authors: Haines
authors: Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Biostatistics, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA.
authors: Lindsay A
authors: LA
authors: Farrer
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors: John
authors: J
authors: Hardy
authors: Norwegian Centre for Dementia Research, Department of Old Age Psychiatry, Oslo University Hospital, Oslo, Norway.
authors: Ingun Dina
authors: ID
authors: Ulstein
authors: Department of Cognitive Science, University of California, San Diego, La Jolla, CA.|NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.|Department of Psychiatry, University of California, San Diego, La Jolla, CA.
authors: Dag
authors: D
authors: Aarsland
authors: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Neurology, Akershus University Hospital, Norway.
authors: Tormod
authors: T
authors: Fladby
authors: Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.|Department of Neurology, St Olav's Hospital, Trondheim University Hospital, Norway.
authors: Linda R
authors: LR
authors: White
authors: Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.|Department of Neurology, St Olav's Hospital, Trondheim University Hospital, Norway.
authors: Sigrid B
authors: SB
authors: Sando
authors: Department of Psychiatry, Haugesund Hospital, Haugesund, Norway.
authors: Arvid
authors: A
authors: Rongve
authors: NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors: Aree
authors: A
authors: Witoelar
authors: Department of Medical Genetics, Oslo University Hospital, Oslo and NORMENT, KG Jebsen Centre for Psychosis Research; Department of Clinical Science, University of Bergen, Bergen, Norway.
authors: Srdjan
authors: S
authors: Djurovic
authors: Department of Neurology, Massachusetts General Hospital, Boston, MA.
authors: Bradley T
authors: BT
authors: Hyman
authors: Department of Geriatric Medicine, University Hospital Reykjavik, Iceland.
authors: Jon
authors: J
authors: Snaedal
authors: deCODE Genetics, Reykjavik, Iceland.
authors: Stacy
authors: S
authors: Steinberg
authors: deCODE Genetics, Reykjavik, Iceland.
authors: Hreinn
authors: H
authors: Stefansson
authors: deCODE Genetics, Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Kari
authors: K
authors: Stefansson
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors: Gerard D
authors: GD
authors: Schellenberg
authors: NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.|Department of Psychiatry, University of California, San Diego, La Jolla, CA.
authors: Ole A
authors: OA
authors: Andreassen
authors: Department of Radiology, University of California, San Diego, La Jolla, CA.|Department of Cognitive Science, University of California, San Diego, La Jolla, CA.|Department of Neurosciences, University of California, San Diego, La Jolla, CA.|NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors: Anders M
authors: AM
authors: Dale
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D050171:Dyslipidemias / Q000150:complications / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics*; D008055:Lipids / Q000097:blood* / Q000235:genetics; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics*; D063994:Peroxisomal Bifunctional Enzyme / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D008055:Lipids; D002097:C-Reactive Protein; D015238:Sulfotransferases; C021350:heparitin sulfotransferase; C576253:EHHADH protein, human; D063994:Peroxisomal Bifunctional Enzyme
keywords: Alzheimer Disease; Genome-Wide Association Study; inflammation; lipids