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JAMA Psychiatry
IMPORTANCE Comorbidities and genetic correlations between gastrointestinal tract diseases
and psychiatric disorders have been widely reported, with the gut-brain axis (GBA)
hypothesized as a potential biological basis. However, the degree to which the shared genetic
determinants are involved in these associations underlying the GBA is unclear.
OBJECTIVE To investigate the shared genetic etiology between gastrointestinal tract diseases
and psychiatric disorders and to identify shared genomic loci, genes, and pathways.
DESIGN, SETTING, AND PARTICIPANTS This genome-wide pleiotropic association study using
genome-wide association summary statistics from publicly available data sources was
performed with various statistical genetic approaches to sequentially investigate the
pleiotropic associations from genome-wide single-nucleotide variation (SNV; formerly
single-nucleotide polymorphism [SNP]), and gene levels and biological pathways to
disentangle the underlying shared genetic etiology between 4 gastrointestinal tract diseases
(inflammatory bowel disease, irritable bowel syndrome, peptic ulcer disease, and
gastroesophageal reflux disease) and 6 psychiatric disorders (schizophrenia, bipolar disorder,
major depressive disorder, attention-deficit/hyperactivity disorder, posttraumatic stress
disorder, and anorexia nervosa). Data were collected from March 10, 2021, to August 25,
2021, and analysis was performed from January 8 through May 30, 2022.
MAIN OUTCOMES AND MEASURES The primary outcomes consisted of a list of genetic loci,
genes, and pathways shared between gastrointestinal tract diseases and psychiatric
disorders.
RESULTS Extensive genetic correlations and genetic overlaps were found among 22 of 24 trait
pairs. Pleiotropic analysis under a composite null hypothesis identified 2910 significant
potential pleiotropic SNVs in 19 trait pairs, with 83 pleiotropic loci and 24 colocalized loci
detected. Gene-based analysis found 158 unique candidate pleiotropic genes, which were
highly enriched in certain GBA-related phenotypes and tissues, whereas pathway enrichment
analysis further highlighted biological pathways primarily involving cell adhesion, synaptic
structure and function, and immune cell differentiation. Several identified pleiotropic loci also
shared causal variants with gut microbiomes. Mendelian randomization analysis further
illustrated vertical pleiotropy across 8 pairwise traits. Notably, many pleiotropic loci were
identified for multiple pairwise traits, such as 1q32.1 (INAVA), 19q13.33 (FUT2), 11q23.2
(NCAM1), and 1p32.3 (LRP8).
CONCLUSIONS AND RELEVANCE These findings suggest that the pleiotropic genetic
determinants between gastrointestinal tract diseases and psychiatric disorders are
extensively distributed across the genome. These findings not only support the shared
genetic basis underlying the GBA but also have important implications for intervention and
treatment targets of these diseases simultaneously.
