Comprehensive Genomic Study Reveals Common Origins for Gastrointestinal Tract Conditions and Mental Health Disorders

 

Comprehensive Genomic Study Reveals Common Origins for Gastrointestinal Tract Conditions and Mental Health Disorders

A groundbreaking Genome-Wide Association Study (GWAS) involving a vast sample of over 3.1 million individuals, aggregated from prior GWAS studies, each comprising at least 50,000 participants, has unearthed significant genetic links connecting gastrointestinal tract diseases, the gut-brain axis (GBA), and psychiatric disorders.

This pioneering research was spearheaded by Weiming Gong, M.M., and a team of researchers affiliated with the Department of Biostatistics at Cheeloo College of Medicine, Shandong University in China. They collaborated closely with the Center for Statistical Genetics at the University of Michigan in Ann Arbor. Their findings were recently featured in JAMA Psychiatry, marking a significant milestone. Although the co-occurrence and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been well-documented, with the GBA theory posited as a pivotal biological foundation, the precise extent of their shared genetic origins remained obscured.

To shed light on these shared genetic determinants, the researchers delved into publicly available data via GWAS, focusing on pleiotropy—a phenomenon where a single genetic locus influences multiple distinct phenotypic traits. They zoomed in 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. Remarkably, these disorders displayed 24 pairs of shared phenotypic traits.

Zhongshang Yuan, Ph.D., the corresponding author, explained, "We found extensive genetic correlations and genetic overlaps among 22 out of the 24 trait pairs."

Their exhaustive analysis pinpointed 158 unique candidate pleiotropic genes. These genes were notably enriched in specific GBA-related phenotypes and tissues. This approach, which zeroes in on groups of genes with shared biological functions, chromosomal locations, or regulation, has the potential to uncover common biological pathways that could be correlated with various diseases and disorders, as opposed to examining individual genes.

It's crucial to recognize that genetics, the gut microbiome, and psychiatric disorders interact intricately. While an individual's genetics can shape their gut microbiome, diet and lifestyle also exert a significant influence. Some gut microbiome variants influenced by diet and lifestyle appear heritable and can affect the health, including mental health, of both mothers and their offspring.

A comprehensive literature review, led by psychiatrist Hamid Tavakoli, M.D., head of consultation-liaison psychiatry services at the Naval Medical Center in Portsmouth, Va., and colleagues in 2021, spotlighted the growing evidence of a connection between depression, anxiety, and other psychiatric disorders and the GBA. Bidirectional interactions occur through the vagus nerve, immune mediators, and bacterial metabolites. Pathophysiological changes in the GBA may trigger the release of inflammatory factors like cytokines, which, in turn, may impact mental health. Although certain studies suggest that probiotics, or "psychobiotics," could alleviate symptoms of specific psychiatric disorders, the evidence is not yet robust enough to provide specific guidance. This has led to the evaluation of specific bacterial strains for distinct disorders.

The extensive pleiotropic analysis featured in the JAMA Psychiatry study bolsters the role of the GBA in overall health and underscores the shared genetic foundations of gastrointestinal and psychiatric disorders, offering promising prospects for targeted interventions.

Intriguingly, single genes, such as FU2, exhibit strong associations with the prevalence of particular bacterial species and the overall composition of the gut microbiome. One of the most striking findings was the high degree of shared variants in the FU2 gene among peptic ulcer disease, schizophrenia, and ADHD. It's conceivable that the FU2 variant, by influencing antigen secretion on mucosal surfaces in the gut, could alter an individual's susceptibility to infectious pathogens, thereby increasing the risk for both ulcers and mental illness.

Nevertheless, the genetic connection between GI and psychiatric diseases remains intricate. Yuan and colleagues observed that another variant in FU2 might elevate the risk of peptic ulcers while reducing the risk of ADHD. Yuan explained, "We hypothesize that treatments targeting FU2 would generate different efficacy on different gastrointestinal tract diseases and psychiatric disorders."