The potential shared role of inflammation in insulin resistance and schizophrenia: A bidirectional two-sample mendelian randomization study

Abstract

Background Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. Methods and findings We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38–6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36–0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37–2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85–1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. Conclusions Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance.

The Potential of Probiotics in the Treatment of Schizophrenia

“…The mechanism of comorbid insulin resistance is still unknown, but observational studies have implicated inflammation in both schizophrenia and insulin resistance [2]. Genome-wide association studies support a role for inflammation as a common cause of schizophrenia and insulin resistance, which could partly explain why the traits commonly co-occur in clinical practice [3]. Probiotics can help regulate the immune system and anti-inflammatory response [4].…”

Variability of glucose, insulin, and lipid disturbances in first-episode psychosis: a meta-analysis

“…Furthermore, understanding the determinants of metabolic variability could provide insight into the biological processes underlying psychosis. For example, a shared role for inflammation in insulin resistance and schizophrenia has been proposed (Perry et al, 2021); however, an inflammatory state may only be seen in a subgroup of patients (Pillinger et al, 2019b), which would explain the metabolic heterogeneity findings documented in the current study. Unfortunately, no studies included in the current meta-analysis provided inflammatory mediator data, precluding a meta-regression analysis exploring the moderating effects of such parameters on metabolic effect size magnitudes.…”

Childhood Immuno-metabolic Markers and Risk of Depression and Psychosis in Adulthood: A Prospective Birth Cohort Study

“…However, in FEP cases Lis et al, (2020) observed a correlation between leptin and cognitive dysfunction, a domain of psychopathology somewhat linked to negative symptoms. Recently, a Mendelian randomisation (MR) study did not find an association between leptin and schizophrenia (Perry et al, 2021a), bringing into question whether leptin plays a causal role in the illness. It is worth noting that this MR analysis relied on GWAS of schizophrenia, and not that of negative symptoms specifically.…”