Treatment Resistance in Schizophrenia Is Associated with Attention Deficit/Hyperactivity Disorder and Gut Microbiota: A Genetic Correlation and Mendelian Randomization Study

Abstract

<b><i>Introduction:</i></b> Observational studies highlight associations of common diseases with individual schizophrenia symptoms. However, it is unclear whether these diseases are associated with individual treatment-resistant schizophrenia (TRS). We aimed to explore the genetic associations between common immune diseases, metabolic diseases, psychiatric disorders, gut microbiota and TRS. <b><i>Methods:</i></b> Genome-wide association study (GWAS) summary data of European participants (<i>n</i> = ∼456,327) included TRS, 11 psychiatric disorders, 23 immune and metabolic diseases, body mass index, height, and 211 gut microbiota. In this genetic correlation and two-sample Mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with common immune diseases, metabolic diseases, psychiatric disorders, and gut microbiota with TRS. <b><i>Results:</i></b> LDSC revealed candidate associations between attention deficit/hyperactivity disorder (ADHD), schizophrenia, intestinal infectious diseases, obesity and TRS (genetic correlation range, 0.230–0.702; <i>p</i> < 0.05). Two-sample MR analyses suggested that ADHD was positively associated with TRS (estimate [SE] = 0.204 [0.073], <i>p</i> = 0.005), a finding that remained stable across statistical models. Besides, schizophrenia and <i>genus Barnesiella</i> levels were causally associated with TRS but not consistent across MR approaches. <b><i>Conclusion:</i></b> This study reports genetic correlations between ADHD, schizophrenia, intestinal infectious diseases, obesity and TRS. The study also found that <i>genus Barnesiella</i> was associated with TRS. These findings may have clinical implications, highlighting the possible strategy for TRS prevention.

Improving precision management of anxiety disorders: a Mendelian randomization study targeting specific gut microbiota and associated metabolites

“…Thanks to large-scale GWAS of gut microbiotas in different diseases, MR has been widely used to study disease pathogenesis. Indeed, several studies using MR have now established that the gut microbiota is strongly associated with several neurological diseases including Alzheimer’s disease ( Zeng et al, 2023 ), major depressive disorder ( Chen M. et al, 2022 ), schizophrenia ( Cheng et al, 2023 ), and insomnia ( Li et al, 2023 ).…”

Gut microbiota and atopic dermatitis: a two-sample Mendelian randomization study

“…Most observational studies have shown that patients with specific dermatitis often have intestinal flora disturbance, but this may only be a clinical symptom of specific dermatitis and cannot prove a causal relationship (observational studies may have differences in intestinal flora due to grouping requirements, sex ratio, ethnicity, etc.). Therefore, MR is adopted to eliminate the interference of confounding factors on the one hand and avoid the influence of reverse causality on the other hand, so as to make the study more rigorous and credible ( 22 ).…”