# Causal Relationship Between Inflammatory Bowel Disease and Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study

## TL;DR

This study finds potential causal links between inflammatory bowel disease and certain neuropsychiatric disorders, supporting the gut-brain connection.

## Contribution

The study uses Mendelian randomization to explore bidirectional causal relationships between IBD and neuropsychiatric disorders.

## Key findings

- IBD and Crohn's disease may cause increased risk of major depressive disorder and schizophrenia.
- Schizophrenia is linked to higher risk of IBD and ulcerative colitis.
- Crohn's disease shows a causal effect on multiple sclerosis, while ulcerative colitis and IBD show bidirectional associations with multiple sclerosis.

## Abstract

Observational studies have indicated a correlation between inflammatory bowel disease (IBD) and neuropsychiatric disorders, yet the causal relationship remains unclear.

We aim to employ two‐sample Mendelian randomization (MR) to ascertain the potential causal relationship between IBD and seven major neuropsychiatric disorders.

We conducted a bidirectional two‐sample MR analysis utilizing genome‐wide association study (GWAS) summary statistics of European ancestry for IBD (31,665 cases and 33,977 controls) and its subtypes, ulcerative colitis (UC, 13,768 cases and 33,977 controls) and Crohn's disease (CD, 17,897 cases and 51,874 controls), along with seven major neuropsychiatric disorders: major depressive disorder (MDD, 135,458 cases and 344,901 controls), bipolar disorder (BD, 41,917 cases and 371,549 controls), schizophrenia (SCZ, 33,640 cases and 43,456 controls), Alzheimer's disease (AD, 39,106 cases and 46,828 controls), Parkinson's disease (PD, 33,674 cases and 449,056 controls), multiple sclerosis (MS, 14,498 cases and 24,091 controls), and amyotrophic lateral sclerosis (ALS, 27,205 cases and 110,881 controls).

Our analysis revealed potential positive causal effects of IBD and CD on MDD and SCZ. Similarly, SCZ was positively correlated with an increased risk of IBD and UC. There was a bidirectional positive association between IBD, UC, and MS, whereas CD showed a positive causal effect on MS. Similar to the investigation of the seven specified neuropsychiatric disorders on CD, we did not find evidence supporting causal effects of MDD, BD, AD, PD, or ALS on IBD or UC. Sensitivity analyses further reinforced the robustness of the MR estimates.

Our results support potential causal relationships between IBD (including its subtypes CD and UC) and several neuropsychiatric disorders, reinforcing the gut‐brain axis concept and enhancing our understanding of extra‐intestinal manifestations of IBD and neuropsychiatric manifestations in the context of IBD.

Forward represents the exploration of potential causal associations between inflammatory bowel disease (IBD)—including ulcerative colitis (UC) and Crohn's disease (CD)—and seven major neuropsychiatric disorders. Reverse indicates the opposite direction of investigation.