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.

Fig 1

MR Analyses Testing Associations between Insulin Resistance Phenotypes (Fasting Insulin (A), Triglycerides (B) and HDL (C)) and Schizophrenia, Highlighting Inflammation-Related SNPs. Points in plots represent the association of the genome-wide significant insulin-resistance single nucleotide polymorphisms (SNPs) and their association with schizophrenia (Y axis) and the exposure (X axis). SNPs are denoted by green points in the plot. Inflammation-related SNPs at genome-wide significance are denoted by a purple border. Inflammation-related SNPs at nominal significance are denoted by a red border. Whiskers represent standard errors. Lines on the plot represent inverse-variance weighted (>1 SNP) or linear regression (1 SNP) of all-SNPs (green line), inflammation-related SNPs at genome-wide significance (purple line) and inflammation-related SNPs at nominal significance (red line).

Fig 2. MR analyses testing associations between cardiometabolic traits and schizophrenia.

Forest plot presents ORs and 95% CIs for associations between cardiometabolic traits and schizophrenia using IVW / Wald Ratio MR analyses based on all single nucleotide polymorphisms (SNPs) associated with each risk factor (green), inflammation-related SNPs at genome-wide significance (purple), and inflammation-related SNPs at nominal significance (red). See Tables 1 and 2 for the number of SNPs used in each analysis. HDL = High Density Lipoprotein; T2DM = Type 2 Diabetes Mellitus; BMI = Body Mass Index; FPG = Fasting Plasma Glucose; LDL = Low-Density Lipoprotein; HbA1C = Glycated Haemoglobin; Glucose Tol = Glucose Tolerance.

Fig 3. Multivariable MR analysis testing associations between insulin resistance phenotypes and schizophrenia after controlling for genetic associations for CRP.

Forest plot presents ORs and 95% CIs for inverse-variance weighted regression (IVW) MR associations between insulin resistance phenotypes and schizophrenia using all single nucleotide polymorphisms (SNPs) (dark green), and after controlling for association of these SNPs with C-reactive protein (CRP) using multivariable MR (MVMR) (light green). The forest plot also presents ORs and 95% CIs for IVW / Wald Ratio MR associations between insulin resistance phenotypes and schizophrenia using inflammation-related SNPs (genome-wide significance = dark purple; nominal significance = red), and after controlling for association of these SNPs with CRP using MVMR (genome-wide significance = light purple; nominal significance = light red). HDL = high-density lipoprotein.