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

• Published in: PLoS medicine 2021-03, Vol.18 (3), p.e1003455
• Main Authors: Perry, Benjamin I, Burgess, Stephen, Jones, Hannah J, Zammit, Stan, Upthegrove, Rachel, Mason, Amy M, Day, Felix R, Langenberg, Claudia, Wareham, Nicholas J, Jones, Peter B, Khandaker, Golam M
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antipsychotics; Biology and Life Sciences; Body mass index; Cardiometabolic Risk Factors; Cholesterol; Development and progression; Diabetes mellitus (non-insulin dependent); Europe; Fasting; Genetic analysis; Genetic aspects; Genome-Wide Association Study; Genomes; Glucose; Glucose tolerance; Hemoglobin; High density lipoprotein; Humans; Inflammation; Inflammation - immunology; Insulin; Insulin resistance; Insulin Resistance - genetics; Laboratory testing; Leptin; Low density lipoprotein; Medicine and Health Sciences; Mendelian Randomization Analysis; Mental disorders; Methods; Middle Aged; Phenotype; Phenotypes; Psychosis; Psychotropic drugs; Risk factors; Schizophrenia; Schizophrenia - genetics; Schizophrenia - immunology; Statistical analysis; Triglycerides; Young Adult; Young adults
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1003455

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. 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 attenuat