Abstract
Type 1 diabetes, particularly with childhood onset, is associated with altered neurocognitive traits, yet the underlying biological mechanisms are unclear. Here, we integrate genome-wide association results with single-cell epigenomic profiles and show that type 1 diabetes heritability is enriched in accessible chromatin of human brain-resident cells, most notably microglia, across neurodevelopment into adulthood. Bonferroni-corrected cross-trait genetic correlation analyses reveal negative correlations of type 1 diabetes with intelligence, executive function, and bipolar disorder, and a positive correlation with myasthenia gravis. Conjunctional false discovery rate analysis identifies pleiotropic loci jointly influencing type 1 diabetes and neurocognitive traits, including the 17q21.31 neurogenomic hub. Mendelian randomization further demonstrates protective effects of educational attainment, intelligence, Alzheimer’s disease, and bipolar disorder on type 1 diabetes risk, whereas liability to multiple sclerosis and myasthenia gravis increases type 1 diabetes risk. In the reverse direction, liability to type 1 diabetes is associated with increased risk of myasthenia gravis. We identify several gene expression regulatory variants in brain and immune cells that jointly influence type 1 diabetes and neurocognitive traits, some of which show concordant differential expression in disease-affected versus control tissue. Together, these findings highlight pleiotropic genetic and neuroimmune mechanisms that link type 1 diabetes with cognition and neuropsychiatric disease risk.
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Data availability
Genome-wide association study (GWAS) summary statistics used in this study are publicly available from the original consortia and repositories listed in Supplementary Table 1, with accession links and/or PMIDs provided. Single-cell ATAC-seq and RNA-seq data are available from the referenced studies as indicated in the Methods. Processed data generated in this work, including results from LDSC, MiXeR, conjunctional false discovery rate, SMR/HEIDI, and Mendelian randomization analyses, are provided in the Supplementary Tables. Source data are provided with this paper.
Code availability
Code for this study is available at GitHub (https://github.com/AlagsLabTeam/T1D-NEURO) and archived at Zenodo82.
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Acknowledgements
This study was supported by Breakthrough T1D grants to DAA (Grant Keys: 5-CDA-2025-1682-S-B and SRA-2024-1472-S-B).
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P.S. and Z.A.S. contributed to the conception and initiation of the project. P.S., Z.A.S., Z.X., Y.D., and B.Z. performed data analyses. D.A.A. conceived, designed, and supervised the study and drafted the manuscript. All authors (P.S., Z.A.S., Z.X., Y.D., A.J., M.S., S.R., B.Z., L.Z., A.T.D., S.A., and D.A.A.) contributed to data interpretation, manuscript review, and approval of the final draft.
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Saarah, P., Syeda, Z.A., Xu, Z. et al. Shared genetic and neuroimmune architecture links type 1 diabetes with neurocognitive traits. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70694-8
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DOI: https://doi.org/10.1038/s41467-026-70694-8
