Causal effects of inflammatory bowel disease on brain structure: A Mendelian randomization study

Brain structural abnormalities are common in patients with Crohn disease (CD) and ulcerative colitis (UC). However, the precise causal relationships between them remain uncertain. Hence, this study aimed to assess the causal effects of CD and UC on brain structure by using Mendelian randomization (MR) analysis. Single nucleotide polymorphisms retrieved from genome-wide association studies are usually selected as instrument variants. In this study, CD and UC-related single nucleotide polymorphisms were used as instrument variants. Two hundred brain imaging-derived phenotypes (IDPs) including regional volume, cortical area and cortical thickness were used as outcome indicators of brain structure. The inverse variance weighting as main method was performed to assess the causal effects. Additionally, potential mediators that may influence brain structure were further investigated by two-step mediation MR analysis. Among 200 IDPs, CD and UC causally influenced 30 IDPs, including regional volume (14 IDPs), cortical area (9 IDPs), and thickness (7 IDPs). In mediation MR analysis, interleukin-6 mediated the causalities from CD to the decreased volume of right frontal operculum, the shrunken area of left banks superior temporal sulcus and right caudal anterior cingulate (mediated proportion = 11.81%, 16.94%, and 11.90%, respectively). C-reactive protein mediated the causalities from CD to the shrunken area of left inferior parietal and from UC to the increased volume of right thalamus (mediated proportion = 3.92% and 5.72%, respectively). This study revealed the causal effects of CD and UC on abnormalities of specific brain regions and indicated that the causal pathways were mediated partly by interleukin-6 or C-reactive protein.