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Shared Genetic and Neuroimaging Signatures between Type 2 Diabetes Mellitus and Intelligence
Background: Type 2 diabetes mellitus (T2DM) has been associated with lower intelligence, yet the ontogenesis of this relationship remains poorly understood. We hypothesized that the two traits share common polygenic profiles (pleiotropy), which further leads to brain structural damage and intelligence decline.
Methods: We analyzed genome-wide association study (GWAS) summary data for T2DM (Ncase = 55,005, Ncontrol = 400,308) and intelligence (N = 269,867) to investigate the genetic relationship between the two traits. Data from the UK Biobank (N = 34,798), including 499 brain imaging-derived phenotypes and intelligence assessments, were integrated to examine brain structure associations. Mediation analysis was performed to explore pathways linking T2DM risk, brain structure, and intelligence.
Findings: Based on the GWAS summary data, we identified a substantial genetic overlap (Dice coefficient = 35%) and a significant negative genetic correlation (rg = -0.16, P = 2.07E-13) between T2DM and intelligence, supporting the notion that higher T2DM risk contributes to lower intelligence. Conjunctional false discovery rate analysis further identified 75 independent loci associated with both traits, with 69% (52/75) of T2DM risk variants being detrimental and 31% (23/75) being protective for intelligence. Furthermore, based on the 34,798 participants from the UK Biobank dataset, 27/75 shared variants (18 detrimental and 9 protective) were replicated. Neuroimaging-trait association analyses revealed 67 shared brain structural features jointly associated with T2DM and intelligence, while 145 features were uniquely associated with intelligence (P < 1.0E-4, Bonferroni correction). Finally, mediation analysis identified seven detrimental pathways linking higher T2DM risk → brain damage → lower intelligence, and six protective pathways explaining higher T2DM risk → brain adaptation → higher intelligence.
Interpretation: These findings shed light on the genetic origins and neurobiological mechanisms connecting T2DM and intelligence, offering insights into the complex relationships between metabolism, brain, and cognitive health.
Funding: This study was supported by the National Natural Science Foundation of China (82472052, 81971599, 82430063, 82030053, 82371924), National Key Research and Development Program of China (2018YFC1314300), Tianjin Natural Science Foundation (19JCYBJC25100, 21JCYBJC01280), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-001A), National Key Project of “Inter55 governmental International Scientific and Technological Innovation Cooperation” (2023YFE0199700), Young Scientific and Technological Talents (Level Three) in Tianjin (QN20230336), Science & Technology Development Fund of Tianjin Education Commission for Higher Education (2019KJ195) and Tianjin Medical University “Clinical Talent Training 123 Climbing Plan”.
Declaration of Interest: The authors declared no potential conflicts of interest.
Ethical Approval: Approval was granted by the National Health and Social Care Information Governance Committee and the NHS Northwest Multicenter Research Ethics Committee to include data from the UKB.
Zhao, Qiyu and Liu, Feng and Du, Xin and Zhang, Yang and Zhao, Guoshu and Zhao, Zhen and Shi, Ziqing and Zhao, Jiaxuan and Wang, Shaoying and Xu, Jiayuan and Qin, Wen and Zhang, Quan, Shared Genetic and Neuroimaging Signatures between Type 2 Diabetes Mellitus and Intelligence. Available at SSRN: https://ssrn.com/abstract=5042345 or http://dx.doi.org/10.2139/ssrn.5042345
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