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Multi-Cohort Transcriptomic Integration Identifies Overlapping Immune and Antigen-Presentation Features in
Shuting Zhong1, Guanfeng Xie1, Zhaohui Zhang1
1Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Background:
Thyroid disorders and Alzheimer's disease (AD) have been linked epidemiologically, but whether AD brain tissue and thyroid tissue affected by Hashimoto's thyroiditis (HT) share molecular features remains unclear.
Methods:
Differential expression was estimated in AD (GSE122063) and HT (GSE138198) discovery cohorts using limma, with donor-level blocking and adjustment for age, sex and post-mortem interval where available. Shared genes were tested against chance within the genes measured in both cohorts, separately for each direction of change; characterized by enrichment analysis; related to marker-based cell-state scores; and evaluated in two AD cohorts, three thyroid cohorts including one with concurrently collected normal thyroid (GSE165724), and a single-nucleus AD dataset (GSE138852).
Results:
The discovery analyses identified 3593 AD- and 3806 HT-associated genes. The overlap was direction-specific: genes upregulated in both diseases exceeded chance (117 vs. 83.2 expected; p = 8.9 × 10-5), whereas the other direction combinations did not. Co-upregulated genes were enriched for MHC class II antigen presentation (FDR = 0.004), complement (FDR = 0.002), microglial activation (FDR = 0.017) and T-cell activation (FDR = 1.7 × 10-4), and recurred in two independent thyroid datasets and the within-study LT+ versus LT- comparison, with less consistent, region-dependent recurrence in AD cohorts. This shared component tracked immune cell-state signals-glial/myeloid activation in AD and lymphocytic infiltration in HT. Fourteen co-upregulated genes, including ITGAX, CD22 and BST2, met prespecified recurrence and detectability criteria.
Conclusions:
AD brain tissue and thyroid tissue affected by HT exhibit a co-upregulated immune and antigen-presentation transcriptional program that reflects immune activation in both tissues. These overlapping features are associative and do not establish a causal relationship between AD and HT.
