A Bi-Directional Mendelian Randomization Study on Five Major Psychiatric Disorders, Inflammatory Regulators, Brain Plasticity, and Related Traits

Introduction Growing evidence links psychiatric disorders to immune system dysfunction, atypical brain development, and psychosocial traits such as intelligence and childhood maltreatment. However, the causal relationships between psychiatric disorders and these potential risk factors remain controversial. Objectives To better elucidate the intertwined pathways underlying five major psychiatric disorders and potential risk factors by employing genetic instruments to evaluate possible causal relationships. Methods We conducted bidirectional two-sample Mendelian randomization (MR) analyses by leveraging summary statistics from recent GWASs with large sample sizes. Causal relationships were estimated between five major psychiatric disorders (ADHD, ASD, BD, MDD, and SCZ) and various factors, including cytokines, longitudinal brain changes, childhood maltreatment, antisocial behavior, educational attainment, and intelligence, which were used as both exposures and outcomes (average N > 310k). LHC-MR, a novel MR method which controls for correlated horizontal pleiotropy and simultaneously estimate bi-directional causal effects for trait pairs, was utilized to discover potential causalities. MRCI, another advanced MR method for estimating reciprocal causal effects, and standard MR methods were employed to replicate the identified significant causalities. Moreover, potential mediating pathways were investigated. Results Causal relationships of 300 trait pairs were examined by LHC-MR, 41 of which achieved significance after multiple testing (p < 1.67e-4). After replication, LHC-MR, MRCI, and standard MR methods agreed on four positive causal effects, including attention-deficit/hyperactivity disorder (ADHD) on the chemokine RANTES and RANTES on major depression (MDD). Mediation analysis further supported that RANTES contributed to the association between ADHD and MDD. Additionally, both schizophrenia and MDD positively increased the risk of childhood maltreatment, perhaps due to premorbid traits which trigger bullying or poor parenting associated with genetic predisposition to these disorders. Conclusions The current study contributes to a better understanding of the intertwined causal network between psychiatric disorders and various risk factors, which may help develop public health prevention and intervention.