Unravelling the joint genetic architecture between psychiatric and insulin-related traits in the general population

Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are heritable disorders that frequently co-occur with insulin resistance (IR)-related conditions. Traditional genetic case-control comparisons are challenged by the extent of heterogeneity and comorbidity within and across these conditions. In this study we step away from univariate analyses to let biology guide us to the potential genetic links between insulin and psychiatry-related traits. We used large-scale population-based genetic studies (N= 17,666-697,734) and applied genomic structural equation modeling to identify the factor structure best representing the joint genetic architecture of symptom scores of ADHD, ASD, and OCD, and five IR-related traits: body mass index (BMI), fasting plasma glucose (FPG), fasting plasma insulin, glycated haemoglobin (HbA1c), and homeostatic model assessment for IR. Subsequently we performed multivariate genome-wide association analyses on the psychiatry-IR related factors to explore genetic associations to unravel its biological basis. Factor analyses indicated that a three-factor model fitted the data best (x2(df=9)=18.79, AIC=56.8, CFI=0.99, SRMR=0.068). One factor included ADHD traits and three IR-related traits (BMI, FPG, HbA1c), while another encompassed OCD traits and HbA1c. The last factor included solely IR-related traits. Gene-wide analyses revealed 57 genes significantly associated with the ADHD-IR factor (p< 2.961e-06) and one gene, MTNR1B (p=3.44e-07), with the OCD/OCS-IR factor. Gene-set analyses found associations with neurodevelopmental pathways. Our findings suggest a shared genetic liability between psychiatric symptoms and IR-related traits in the general population, offering new perspectives on the molecular genetics underlying the overlap between psychiatric and IR-related somatic conditions as well as biologically informed clustering within psychiatry.