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Shared genetic etiologies between type 1 diabetes and neurobiological traits

Poster Session F - Tuesday, April 1, 2025, 8:00 – 10:00 am EDT, Back Bay Ballroom/Republic Ballroom

David Alagpulinsa^1,2, Priscilla Priscilla Saarah^1,2, Zehra Syeda^1,2, Ziang Xu^1,2, Yikai Dong^1,2, Samira Asgari^3,4, Andrew DeWan^5,6; ¹Yale Center for Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, USA., ²Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA., ³Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA., ⁴Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., ⁵Center for Perinatal, Pediatric and Environmental Epidemiology, 60 College Street, Yale School of Public Health, New Haven, CT 06510, United States., ⁶Department of Chronic Disease Epidemiology, Yale School of Public Health, 60 College Street, New Haven, CT 06510, United States.

Epidemiological observations have reported accelerated and/or high prevalence of nearly every neuropsychiatric disorder in patients with type 1 diabetes (T1D). The biological mechanisms underlying this association remain unclear. We examined whether shared genetic factors contribute to the clinical overlap between T1D and neurophenotypes using state-of-the-art statistical genetic analyses of large-scale genome-wide association studies (GWAS) summary data for T1D and 24 distinct neuropsychiatric traits, as well as single-blood and brain cell expression quantitative trait loci (eQTL) data. We found that T1D shares significant genome-wide genetic architecture with several neurophenotypes, including multiple sclerosis, myasthenia gravis, migraine, insomnia, autism-spectrum disorder, bipolar disorder, educational attainment, and intelligence. Several T1D risk loci were identified as being jointly associated with these neurophenotypes. Summary-data-based Mendelian randomization and heterogeneity in independent instruments analysis revealed potential causal genes shared by T1D and neurophenotypes, including RPS26, LRRC37A2, ARL17A, CRHR1-IT1, LRRC37A2, DNDP1, PLEKHM1, RP11-25918.3, RP11-707023.3, RP11-259G18.2, KANSL1-AS1 and LRCC37A49. We showed that while genetic liability to T1D is associated with risk of only migraine and myasthenia gravis, several genetically proxied neurophenotypes are associated with risk of T1D, including increased risk in multiple sclerosis, myasthenia gravis, attention deficit/hyperactive disorder, obsessive-compulsive disorder, Parkinson’s disease, and short sleep duration, and reduced risk in bipolar disorder, education, and intelligence. These findings highlight shared genetic factors that may contribute to the clinical overlap between T1D and neuropsychiatric traits and informs consideration of neuropsychiatric risk in T1D management.

Topic Area: METHODS: Other