Glucose and Insulin-Related Traits, Type 2 Diabetes and Risk of Schizophrenia: A Mendelian Randomization Study

BACKGROUND: The link between schizophrenia and diabetes mellitus is well established by observational studies; however, the cause-effect relationship remains unclear. METHODS: Here, we conducted Mendelian randomization analyses to assess a causal relationship of the genetic variants related to elevated fasting glucose levels, hemoglobin A(1c) (HbA(1c)), fasting insulin levels, and type 2 diabetes with the risk of schizophrenia. The analyses were performed using summary statistics obtained for the variants identified from the genome-wide association meta-analyses of fasting glucose levels (up to 133,010 individuals), HbA(1c) (up to 153,377 individuals), fasting insulin levels (up to 108,557 individuals), type 2 diabetes (up to 659,316 individuals), and schizophrenia (up to 108,341 individuals). The association between each variant and schizophrenia was weighted by its association with each studied condition, and estimates were combined using an inverse-variance weighted meta-analysis. FINDINGS: Using information from thirteen variants related to fasting insulin levels, the causal effect of fasting insulin levels increases (per 1-SD) on the risk of schizophrenia was estimated at an odds ratio (OR) of 2·33 (p = 0·001), which is consistent with findings from the observational studies. The fasting glucose associated single nucleotide polymorphisms (SNPs) had no effect on the risk of schizophrenia in Europeans and East Asians (p > 0·05). Nonsignificant effects on the risk of schizophrenia was observed with raised HbA(1c) and type 2 diabetes, and consistent estimates were obtained across different populations. INTERPRETATION: Our results suggest a causal role of elevated fasting insulin levels in schizophrenia pathogenesis.