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

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.

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.

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.