title: Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease.
abstract: Late-onset Alzheimer disease (AD), the most common form of dementia, places a large burden on families and society. Although epidemiological and clinical evidence suggests a relationship between inflammation and AD, their relationship is not well understood and could have implications for treatment and prevention strategies.
  
  
  
  To determine whether a subset of genes involved with increased risk of inflammation are also associated with increased risk for AD.
  
  
  
  In a genetic epidemiology study conducted in July 2015, we systematically investigated genetic overlap between AD (International Genomics of Alzheimer's Project stage 1) and Crohn disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, and psoriasis using summary data from genome-wide association studies at multiple academic clinical research centers. P values and odds ratios from genome-wide association studies of more than 100 000 individuals were from previous comparisons of patients vs respective control cohorts. Diagnosis for each disorder was previously established for the parent study using consensus criteria.
  
  
  
  The primary outcome was the pleiotropic (conjunction) false discovery rate P value. Follow-up for candidate variants included neuritic plaque and neurofibrillary tangle pathology; longitudinal Alzheimer's Disease Assessment Scale cognitive subscale scores as a measure of cognitive dysfunction (Alzheimer's Disease Neuroimaging Initiative); and gene expression in AD vs control brains (Gene Expression Omnibus data).
  
  
  
  Eight single-nucleotide polymorphisms (false discovery rate P < .05) were associated with both AD and immune-mediated diseases. Of these, rs2516049 (closest gene HLA-DRB5; conjunction false discovery rate P = .04 for AD and psoriasis, 5.37 × 10-5 for AD, and 6.03 × 10-15 for psoriasis) and rs12570088 (closest gene IPMK; conjunction false discovery rate P = .009 for AD and Crohn disease, P = 5.73 × 10-6 for AD, and 6.57 × 10-5 for Crohn disease) demonstrated the same direction of allelic effect between AD and the immune-mediated diseases. Both rs2516049 and rs12570088 were significantly associated with neurofibrillary tangle pathology (P = .01352 and .03151, respectively); rs2516049 additionally correlated with longitudinal decline on Alzheimer's Disease Assessment Scale cognitive subscale scores (β [SE], 0.405 [0.190]; P = .03). Regarding gene expression, HLA-DRA and IPMK transcript expression was significantly altered in AD brains compared with control brains (HLA-DRA: β [SE], 0.155 [0.024]; P = 1.97 × 10-10; IPMK: β [SE], -0.096 [0.013]; P = 7.57 × 10-13).
  
  
  
  Our findings demonstrate genetic overlap between AD and immune-mediated diseases and suggest that immune system processes influence AD pathogenesis and progression.
authors.affiliation: Department of Neurology, University of California, San Francisco.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.affiliation: Department of Psychiatry, Washington University, St Louis, Missouri3Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cognitive Sciences, University of California, San Diego, La Jolla.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schork
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla.
authors.forename: Wesley K
authors.initials: WK
authors.lastname: Thompson
authors.affiliation: Department of Psychiatry, Washington University, St Louis, Missouri.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.affiliation: Department of Psychiatry, Washington University, St Louis, Missouri.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Radiology, University of California, San Diego, La Jolla.
authors.forename: Linda K
authors.initials: LK
authors.lastname: McEvoy
authors.affiliation: Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway8Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Aree
authors.initials: A
authors.lastname: Witoelar
authors.affiliation: Department of Radiology, University of California, San Diego, La Jolla.
authors.forename: Chi-Hua
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Dominic
authors.initials: D
authors.lastname: Holland
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla6Department of Radiology, University of California, San Diego, La Jolla.
authors.forename: James B
authors.initials: JB
authors.lastname: Brewer
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco.
authors.forename: William P
authors.initials: WP
authors.lastname: Dillon
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco.
authors.forename: Pratik
authors.initials: P
authors.lastname: Mukherjee
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hess
authors.affiliation: Department of Neurology, University of California, San Francisco.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Miller
authors.affiliation: Department of Neurology, University of California, San Francisco.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Bonham
authors.affiliation: Department of Neurology, University of California, San Francisco.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Neurology, University of California, San Francisco.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
authors.affiliation: Department of Neurology, University of California, San Francisco.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.affiliation: Department of Neurology, University of California, San Francisco.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Norwegian PSC Research Center and KG Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway14Division of Gastroenterolog.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway8Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla4Department of Cognitive Sciences, University of California, San Diego, La Jolla5Department of Psychiatry, University of California, San Diego, La Jolla6Department of Radiology, Uni.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco.
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Desikan
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D059847:HLA-DRB5 Chains / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000235:genetics*; D008297:Male; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D059847:HLA-DRB5 Chains; D017853:Phosphotransferases (Alcohol Group Acceptor); C434257:inositol polyphosphate multikinase