Shared genetics and bidirectional causal relationships between type 2 diabetes and attention-deficit/hyperactivity disorder

BACKGROUND: Type 2 diabetes (T2D) is a chronic metabolic disorder with high comorbidity with mental disorders. The genetic links between attention-deficit/hyperactivity disorder (ADHD) and T2D have yet to be elucidated. AIMS: We aim to assess shared genetics and potential associations between ADHD and T2D. METHODS: We performed genetic correlation, two-sample Mendelian randomisation and polygenic overlap analyses between ADHD and T2D. The genome-wide association study (GWAS) summary results of T2D (80 154 cases and 853 816 controls), ADHD2019 (20 183 cases and 35 191 controls from the 2019 GWAS ADHD dataset) and ADHD2022 (38 691 cases and 275 986 controls from the 2022 GWAS ADHD dataset) were used for the analyses. The T2D dataset was obtained from the DIAGRAM Consortium. The ADHD datasets were obtained from the Psychiatric Genomics Consortium. We compared genome-wide association signals to reveal shared genetic variation between T2D and ADHD using the larger ADHD2022 dataset. Moreover, molecular pathways were constructed based on large-scale literature data to understand the connection between ADHD and T2D. RESULTS: T2D has positive genetic correlations with ADHD2019 (r(g)=0.33) and ADHD2022 (r(g)=0.31). Genetic liability to ADHD2019 was associated with an increased risk for T2D (odds ratio (OR): 1.30, p<0.001), while genetic liability to ADHD2022 had a suggestive causal effect on T2D (OR: 1.30, p=0.086). Genetic liability to T2D was associated with a higher risk for ADHD2019 (OR: 1.05, p=0.001) and ADHD2022 (OR: 1.03, p<0.001). The polygenic overlap analysis showed that most causal variants of T2D are shared with ADHD2022. T2D and ADHD2022 have three overlapping loci. Molecular pathway analysis suggests that ADHD and T2D could promote the risk of each other through inflammatory pathways. CONCLUSIONS: Our study demonstrates substantial shared genetics and bidirectional causal associations between ADHD and T2D.