Large Genomic Analysis Finds Shared Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders

A genome-wide association study (GWAS) with a sample size of more than 3.1 million individuals drawn from prior GWAS studies of at least 50,000 found significant genetic correlations between gastrointestinal tract diseases, the gut-brain axis (GBA), and psychiatric disorders.

The study by Weiming Gong, M.M., and colleagues was conducted by the Department of Biostatistics at Cheeloo College of Medicine at Shandong University in China in collaboration with the Center for Statistical Genetics of the University of Michigan in Ann Arbor and was published earlier this year in JAMA Psychiatry. While comorbidities and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been widely documented with the GBA postulated as a key biological basis, the extent to which these disorders share genetic etiology has remained unclear.

The authors used publicly available data employing GWAS to do a pleiotropic analysis aimed at pinpointing shared genomic loci, genes, and pathways. Pleiotropy is the phenomenon in which a single genetic locus affects two or more distinct phenotypic traits.

In order to explore underlying shared genetic determinants, the study focused on four gastrointestinal tract diseases—inflammatory bowel disease, irritable bowel syndrome, peptic ulcer disease, and gastroesophageal reflux disease—and six psychiatric disorders: schizophrenia, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder (ADHD), posttraumatic stress disorder, and anorexia nervosa. These disorders shared 24 pairs of phenotypic traits.

“We found extensive genetic correlations and genetic overlaps among 22 out of the 24 trait pairs,” corresponding author Zhongshang Yuan, Ph.D., told Psychiatric News.

A total of 158 unique candidate pleiotropic genes were identified, which were highly enriched, or overrepresented, in certain GBA-related phenotypes and tissues, Yuan observed. The focus on groups of genes that share common biological function, chromosomal location, or regulation—as opposed to single-gene analysis—helps scientists identify common biological pathways that may be correlated with various diseases or disorders.

In exploring the interaction between genetics, the gut microbiome, and psychiatric disorders, it is important to keep in mind that while an individual’s genetics shapes the gut microbiome, diet and lifestyle also play an important role, said Yuan. Some variants in the gut microbiome spurred by diet and lifestyle appear heritable and are likely to affect the health—including the mental health—of both mother and offspring.

In a wide-ranging literature review published in 2021, psychiatrist Hamid Tavakoli, M.D., head of consultation-liaison psychiatry services at the Naval Medical Center in Portsmouth, Va., and colleagues, discussed growing evidence of the link between depression, anxiety, and other psychiatric disorders and the GBA, where bidirectional interaction occurs via the vagus nerve, immune mediators, and bacterial metabolites.

Pathophysiology in the GBA may, for example, induce the release of inflammatory factors, such as cytokines, which, in turn, may influence mental health. While a number of studies have found that the use of probiotics, in particular, may improve symptoms of specific psychiatric disorders, the evidence at this point is not robust enough to provide specific guidance. The use of probiotics to ameliorate psychiatric conditions, known as psychobiotics, has led to the evaluation of specific bacterial strains for specific disorders, according to Tavakoli and colleagues in the 2021 study.

The large-scale pleiotropic analysis described in the JAMA Psychiatry study provides more evidence for the role of the GBA in health and the shared genetic underpinnings of gastrointestinal and psychiatric disorders, as well as the potential for targeted interventions.

Single genes—for example FU2—are strongly associated with the prevalence of certain bacterial species and the overall composition of the gut microbiome. Among the most striking associations found in this study were that variants in the FU2 gene were highly shared between peptic ulcer disease, schizophrenia, and ADHD, Yuan noted. It is possible that the FU2 variant, by altering the secretion of antigens on mucosal surfaces in the gut, could alter host susceptibility to infectious pathogens and put an individual at increased risk for both ulcers and mental illness.

Yet the genetic connection between GI and psychiatric disease is never simple: Yuan and colleagues noted that another variant in FU2 may increase the risk of peptic ulcers but decrease the risk for ADHD. “We hypothesize that treatments targeting FU2 would generate different efficacy on different gastrointestinal tract diseases and psychiatric disorders,” Yuan said.

Funding and support for this study was provided by the National Natural Science Foundation of China; the Taishan Scholar Project of Shandong Province; and the Cheeloo Young Talent Program of Shandong University. ■