Shared genetic and neuroimmune architecture links type 1 diabetes with neurocognitive traits

Type 1 diabetes (T1D), particularly with childhood onset, is associated with altered cognitive traits and neuropsychiatric risk, yet the biological bases remain unclear. Here, we integrate genome-wide association variants with single-cell epigenomic profiles and show that T1D heritability is enriched in accessible chromatin of human brain-resident cells, notably microglia, across neurodevelopment into adulthood. FDR-corrected cross-trait genetic correlation analyses revealed negative correlations of T1D with intelligence, executive function, and bipolar disorder, and a positive correlation with myasthenia gravis. Joint association analyses identified pleiotropic loci influencing both T1D and neurocognitive traits, including the neurogenomic hub 17q21.31. FDR-corrected Mendelian randomization further demonstrated protective effects of educational attainment, intelligence, Alzheimer’s disease, and bipolar disorder on T1D risk, while multiple sclerosis, myasthenia gravis, obsessive-compulsive disorder, short sleep duration, and attention-deficit/hyperactivity disorder increased T1D risk. In the reverse direction, T1D liability was associated with increased risk of myasthenia gravis and migraine, and reduced risk of schizophrenia and bipolar disorder. Genetic regulation of several brain- and immune-expressed genes, notably within 17q21.31, jointly influences T1D and neurocognitive traits, with some showing differential expression in disease-affected versus control tissue. Together, these findings highlight pleiotropic genetic and neuroimmune mechanisms that link T1D with both cognition and neuropsychiatric disease risk.

Type 1 diabetes (T1D) is characterized by T cell-mediated destruction of insulin-producing pancreatic beta cells, necessitating lifelong dependence on insulin therapy to control glycemia. Despite advances in management, people with T1D lose more than a decade of life expectancy [1,2] and over two decades of healthy life [3] compared with the general population.

Cognitive deficits—which are antecedents and characteristic symptoms of neuropsychiatric disorders—are consistently more prevalent in people with T1D than in the general population [4,5]. Childhood-onset T1D is particularly associated with cognitive deficits, including reduced working memory, executive function, and performance IQ [6–9]. Children with T1D often underachieve academically compared to their peers [10–12], with even poorer outcomes in those with co-occurring psychiatric disorders [10]. Neuroimaging studies support these findings, showing reduced gray and white matter volumes in children with T1D [13–15]. Adults with T1D also exhibit accelerated cognitive decline [16,17] and smaller total brain volumes [17]. Epidemiological studies further demonstrate higher rates of psychiatric disorders in people with T1D compared to the general population [12,18–20].

Because hyperglycemia is the defining pathology of T1D, research has emphasized its effects on brain development and function, identifying correlations between poor glycemic control and cognitive or psychiatric comorbidities [9,21–24]. This view has reinforced the idea that T1D-associated neurocognitive deficits arise primarily as complications of dysglycemia [9,15,25–28]. However, both T1D [29] and cognitive or neuropsychiatric disorders [30] are highly heritable—up to ∼50% and 80%, respectively. Despite this substantial heritability, the extent to which shared genetic architecture contributes to their comorbidity remains largely unexplored.

Observational studies are prone to confounding by sociodemographic factors and reverse causality—for example, impaired executive function may reduce adherence to glycemic control and exacerbate disease outcomes. Moreover, because T1D is frequently diagnosed during childhood or adolescence—a critical window for neurodevelopment [25–28,31]—clarifying whether shared genetic mechanisms jointly influence T1D and neurodevelopmental outcomes is essential.

In this study, we systematically investigate the shared genetic and cellular architecture between T1D and neurocognitive traits. By integrating genome-wide association data with single-cell epigenomic annotations, we demonstrate that T1D heritability is significantly enriched in accessible chromatin regions of brain-resident cells, particularly microglia. We further identify pleiotropic loci, genes, and genetically regulated expression patterns that converge on neuroimmune pathways, pointing to a shared genetic basis linking T1D with neurocognitive outcomes. Notably, these include the 17q21.31 locus—previously implicated in neurodevelopment and psychiatric disorders—which emerges as a key genomic hub of T1D– neurocognitive convergence.

Disclaimer: This manuscript is a preprint and has not been certified by peer review. It reports new research that has yet to be evaluated and should not be used to guide clinical practice.

medRxiv Categories: Genetic and Genomic Medicine; Neurology/Psychiatry; Immunology