Genetic correlation, shared loci, but no causality between bipolar disorder and inflammatory bowel disease: A genome-wide pleiotropic analysis

Background and aims: The comorbidity between bipolar disorder (BD) and inflammatory bowel disease (IBD) has been widely reported in observational studies. However, unclear whether this comorbidity reflects a shared genetic architecture. Methods: Leveraging large-scale genome-wide association study (GWAS) summary statistics of BD, IBD and its subtypes, ulcerative colitis (UC) and Crohn's disease (CD), we performed a genome-wide pleiotropic analysis to estimate heritability and genetic correlation, identify pleiotropy loci/genes, and explore the shared biological pathway. Mendelian randomization (MR) studies were subsequently employed to infer whether the potential causal relationship is present. Results: We found a positive significant genetic correlation between BD and IBD (rg = 0.10, P = 7.00 x 10- 4), UC (rg = 0.09, P = 2.90 x 10-3), CD (rg = 0.08, P = 6.10 x 10-3). In cross-trait meta-analysis, a total of 29, 24, and 23 independent SNPs passed the threshold for significant association between BD and IBD, UC, and CD, respectively. We identified five novel pleiotropy genes including ZDHHC2, SCRN1, INPP4B, C1orf123, and BRD3 in both BD and IBD, as well as in its subtypes UC and CD. Pathway enrichment analyses revealed that those pleiotropy genes were mainly enriched in several immune-related signal transduction pathways and cerebral disease-related pathways. MR analyses provided no evidence for a causal relationship between BD and IBD. Conclusion: Our findings corroborated that shared genetic basis and common biological pathways may explain the comorbidity of BD and IBD. These findings further our understanding of shared genetic mechanisms underlying BD and IBD, and potentially provide points of intervention that may allow the development of new therapies for these co-occurrent disorders.