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Title | Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Yokoyama JS, Wang Y, Schork AJ, Thompson WK, Karch CM, Cruchaga C, McEvoy LK, Witoelar A, Chen C-H, Holland D, Brewer JB, Franke A, Dillon WP, Wilson DM, Mukherjee P, Hess CP, Miller Z, Bonham LW, Shen J, Rabinovici GD, Rosen HJ, Miller BL, Hyman BT, Schellenberg GD, Karlsen TH, Andreassen OA, Dale AM, Desikan RS |
Corporate Authors | Alzheimer’s Disease Neuroimaging Initiative |
Journal | JAMA Neurol |
Volume | 73 |
Issue | 6 |
Pagination | 691-7 |
Date Published | 2016 06 01 |
ISSN | 2168-6157 |
Keywords | Alzheimer Disease, Cognition Disorders, Female, Genome-Wide Association Study, HLA-DRB5 Chains, Humans, Inflammation, Male, Phosphotransferases (Alcohol Group Acceptor), Polymorphism, Single Nucleotide |
Abstract | IMPORTANCE: 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.OBJECTIVE: To determine whether a subset of genes involved with increased risk of inflammation are also associated with increased risk for AD.DESIGN, SETTING, AND PARTICIPANTS: 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.MAIN OUTCOMES AND MEASURES: 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).RESULTS: 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).CONCLUSIONS AND RELEVANCE: Our findings demonstrate genetic overlap between AD and immune-mediated diseases and suggest that immune system processes influence AD pathogenesis and progression. |
DOI | 10.1001/jamaneurol.2016.0150 |
Alternate Journal | JAMA Neurol |
PubMed ID | 27088644 |
PubMed Central ID | PMC4905783 |
Grant List | P30 AG010124 / AG / NIA NIH HHS / United States P50 AG023501 / AG / NIA NIH HHS / United States RC2 AG036528 / AG / NIA NIH HHS / United States K01 AG049152 / AG / NIA NIH HHS / United States K24 AG045333 / AG / NIA NIH HHS / United States P50 AG005131 / AG / NIA NIH HHS / United States R01 GM104400 / GM / NIGMS NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States U24 AG041689 / AG / NIA NIH HHS / United States P01 AG019724 / AG / NIA NIH HHS / United States K01 AG046374 / AG / NIA NIH HHS / United States R01 HD061414 / HD / NICHD NIH HHS / United States R01 AG045611 / AG / NIA NIH HHS / United States RC2 DA029475 / DA / NIDA NIH HHS / United States |