Mendelian Randomization and Double Machine Learning Modeling Reveal Brain Imaging-Derived Phenotypes as Functional...

Autoimmune inflammatory diseases (AIDs) are genetically linked disorders with unclear causal links to brain functional networks. Using bidirectional two-sample Mendelian randomization (MR) on GWAS data from 18 AIDs and 1,366 brain imaging-derived phenotypes (n = 8,428), we identified significant associations, including reduced left striatal activity increasing multiple sclerosis risk (OR = 0.59), left uncinate fasciculus activity elevating systemic lupus erythematosus risk (OR = 3.72), and asymmetric cerebellar peduncle effects in cutaneous vasculitis (left: OR = 0.11; right: OR = 8.57) [exploratory finding with 24.8%-37.8% power]. Fibromyalgia suppressed cerebellar area VIIIa (β = -0.023). Sensitivity analyses, double machine learning, and >99% statistical power supported robustness. These findings suggest alterations in default mode, salience, and central executive networks contribute to AIDs pathogenesis, highlighting brain regions such as the striatum and cerebellar peduncles as potential therapeutic targets.