Dissecting causal relationships between cortical morphology and neuropsychiatric disorders: a bidirectional Mendelian randomization study

Brain cortical morphology, indexed by its surface area and thickness, is known to be highly heritable. Previous research has suggested a relationship of cortical morphology with several neuropsychiatric phenotypes. However, the multitude of potential confounders makes it difficult to establish causal relationships. Here we employ generalized summary-data-based Mendelian randomization and a series of sensitivity analyses to investigate causal links between 70 cortical morphology measures and 199 neuropsychiatric, behavioral and metabolic phenotypes. We show that total brain cortical surface area (TSA) has significant positive causal effects on 18 phenotypes. The strongest effects include TSA positively influencing cognitive performance, while reverse analyses reveal small effects of cognitive performance on TSA. Global mean cortical thickness (MTH) exhibits significant causal effects on five phenotypes, including schizophrenia. MTH reduces schizophrenia risk, and bidirectional causality is found between MTH and smoking initiation. Finally, in regional analyses, we detect positive influences of the transverse temporal surface area on cognitive performance and negative influences of transverse temporal thickness on schizophrenia risk. Overall, our results highlight bidirectional associations between TSA, MTH and neuropsychiatric traits. These insights offer potential avenues for intervention studies aimed at improving brain health.