The human cerebral cortex morphology in neuropsychiatric disorders: A causal inference based on Mendelian Randomization

Background: Neuropsychiatric disorders, including Alzheimer's disease (AD), major depressive disorder (MDD), anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, insomnia, and schizophrenia (SCZ), are prevalent and impose substantial morbidity and mortality worldwide. Brain morphometry, is increasingly recognized for its relevance to cognitive, emotional, and behavioral functions, yet its causal links to neuropsychiatric pathologies are not well established. Objective: This study aimed to explore the causal relationships between cortical thickness (TH) and surface area (SA) with 7 neuropsychiatric disorders using Mendelian randomization (MR) analyses. Methods: We employed data from genome-wide association studies (GWAS) comprising 51,665 individuals to evaluate cortical SA and TH. We selected single nucleotide polymorphisms (SNPs) as instrumental variables for MR analyses to investigate the causal associations with neuropsychiatric disorders. Results: Increased TH in the paracentral cortex was associated with a reduced risk of ADHD. Similarly, a thicker temporal pole was linked to a lower risk of MDD. The TH of the lingual region showed an inverse association with anxiety disorders. The SA of the fusiform gyrus was associated with AD risk, and morphological variations in the caudal middle frontal cortex, isthmus cingulate cortex, and temporal pole were correlated with bipolar disorder risk. An increased TH of the posterior cingulate cortex was associated with higher insomnia risk, and the TH of the pericalcarine region negatively correlated with SCZ risk. Conclusion: This research provided novel evidence for the causal role of cerebral cortex morphology in neuropsychiatric disorders, suggesting potential targets for therapeutic intervention.