Abstract
Background
Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia, and are the 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 seven 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; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multi-variable Mendelian randomization (MR) analysis to test whether: (i) ten cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an IR phenotype, and seven 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; (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 (Inverse Variance Weighted (IVW) OR=2.76, 95% C.I, 1.08-7.11, Holm-Bonferroni corrected p-value (p)=0.040), raised triglycerides (IVW OR=2.86, 95% C.I., 1.23-6.66, p-=0.035), lower high-density lipoprotein (IVW OR=0.52, 95% C.I., 0.33-0.82; p¬=0.030)) was associated with schizophrenia. Evidence for these associations attenuated completely in multi-variable MR analyses after adjusting for C-reactive protein (CRP), an archetypal inflammatory marker: (fasting insulin IVW OR=0.95, 95% C.I, 0.55-1.62, p=0.645), triglycerides (IVW OR=0.79, 95% C.I., 0.58-1.21, p¬=0.203) and lower high-density lipoprotein (IVW OR=1.48, 95% C.I., 0.66-3.33; p¬=0.340), 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.
Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia, and are the 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 seven 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; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multi-variable Mendelian randomization (MR) analysis to test whether: (i) ten cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an IR phenotype, and seven 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; (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 (Inverse Variance Weighted (IVW) OR=2.76, 95% C.I, 1.08-7.11, Holm-Bonferroni corrected p-value (p)=0.040), raised triglycerides (IVW OR=2.86, 95% C.I., 1.23-6.66, p-=0.035), lower high-density lipoprotein (IVW OR=0.52, 95% C.I., 0.33-0.82; p¬=0.030)) was associated with schizophrenia. Evidence for these associations attenuated completely in multi-variable MR analyses after adjusting for C-reactive protein (CRP), an archetypal inflammatory marker: (fasting insulin IVW OR=0.95, 95% C.I, 0.55-1.62, p=0.645), triglycerides (IVW OR=0.79, 95% C.I., 0.58-1.21, p¬=0.203) and lower high-density lipoprotein (IVW OR=1.48, 95% C.I., 0.66-3.33; p¬=0.340), 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.
| Original language | English |
|---|---|
| Journal | PLoS Medicine |
| Publication status | Published - 1 Oct 2020 |
