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Original Investigation |

Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease

Jennifer S. Yokoyama, PhD1; Yunpeng Wang, PhD2,3; Andrew J. Schork, MS4; Wesley K. Thompson, PhD5; Celeste M. Karch, PhD2; Carlos Cruchaga, PhD2; Linda K. McEvoy, PhD6; Aree Witoelar, PhD7,8; Chi-Hua Chen, PhD6; Dominic Holland, PhD3; James B. Brewer, MD, PhD3,6; Andre Franke, PhD9; William P. Dillon, MD10; David M. Wilson, MD, PhD10; Pratik Mukherjee, MD, PhD10; Christopher P. Hess, MD, PhD10; Zachary Miller, MD1; Luke W. Bonham, BS1; Jeffrey Shen, BS1; Gil D. Rabinovici, MD1; Howard J. Rosen, MD1; Bruce L. Miller, MD1; Bradley T. Hyman, MD, PhD11; Gerard D. Schellenberg, PhD12; Tom H. Karlsen, MD, PhD13,14; Ole A. Andreassen, MD, PhD7,8; Anders M. Dale, PhD3,4,5,6; Rahul S. Desikan, MD, PhD10 ; for the Alzheimer’s Disease Neuroimaging Initiative
[+] Author Affiliations
1Department of Neurology, University of California, San Francisco
2Department of Psychiatry, Washington University, St Louis, Missouri
3Department of Neurosciences, University of California, San Diego, La Jolla
4Department of Cognitive Sciences, University of California, San Diego, La Jolla
5Department of Psychiatry, University of California, San Diego, La Jolla
6Department of Radiology, University of California, San Diego, La Jolla
7Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
8Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
9Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
10Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco
11Department of Neurology, Massachusetts General Hospital, Boston
12Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia
13Norwegian 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, Norway
14Division of Gastroenterology, Institute of Medicine, University of Bergen, Bergen, Norway
JAMA Neurol. 2016;73(6):691-697. doi:10.1001/jamaneurol.2016.0150.
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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.

Figures in this Article


Place holder to copy figure label and caption
Figure 1.
Single-Nucleotide Polymorphism Enrichment for Alzheimer Disease (AD) Across Different Levels of Significance

Conditional quantile-quantile (Q-Q) plots of nominal −log10(P) vs empirical −log10(q) (corrected for inflation) in AD below the standard genome-wide association study threshold of P < 5 × 10−8 as a function of significance of association with Crohn disease (CD) (A), ulcerative colitis (UC) (B), type 1 diabetes (T1D) (C), rheumatoid arthritis (RA) (D), celiac disease (CeD) (E), and psoriasis (PSOR) (F) at the level of −log10(P) ≥ 0.0, −log10(P) ≥ 1.0, −log10(P) ≥ 2.0, and −log10(P) ≥ 3.0 corresponding to P ≤ 1, P ≤ .1, P ≤ .01, and P ≤ .001, respectively. Dashed line indicates all single-nucleotide polymorphisms.

Graphic Jump Location
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Figure 2.
Shared Genetic Risk Between Alzheimer Disease (AD) and Immune-Mediated Diseases

Conjunction Manhattan plot of conjunctional –log10(false discovery rate P value) for AD given Crohn disease (CD), ulcerative colitis (UC), type 1 diabetes (T1D), rheumatoid arthritis (RA), celiac disease (CeD), and psoriasis (PSOR). Single-nucleotide polymorphisms with conjunctional –log10(false discovery rate P value) > 1.3 (ie, false discovery rate P < .05) are shown with large points. A black line around the large points indicates the most significant single-nucleotide polymorphism in each linkage disequilibrium block; these single-nucleotide polymorphisms were each annotated with the closest gene, which is listed with the symbol in each locus. For additional details, see eAppendix 2 in the Supplement.

Graphic Jump Location




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