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Investigation of glycaemic traits in psychiatric disorders using Mendelian randomisation revealed a causal relationship with anorexia nervosa

Abstract

Data from observational studies have suggested an involvement of abnormal glycaemic regulation in the pathophysiology of psychiatric illness. This may be an attractive target for clinical intervention as glycaemia can be modulated by both lifestyle factors and pharmacological agents. However, observational studies are inherently confounded, and therefore, causal relationships cannot be reliably established. We employed genetic variants rigorously associated with three glycaemic traits (fasting glucose, fasting insulin, and glycated haemoglobin) as instrumental variables in a two-sample Mendelian randomisation analysis to investigate the causal effect of these measures on the risk for eight psychiatric disorders. A significant protective effect of a natural log transformed pmol/L increase in fasting insulin levels was observed for anorexia nervosa after the application of multiple testing correction (OR = 0.48 [95% CI: 0.33-0.71]—inverse-variance weighted estimate). There was no consistently strong evidence for a causal effect of glycaemic factors on the other seven psychiatric disorders considered. The relationship between fasting insulin and anorexia nervosa was supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between insulin levels and anorexia.

a Forest plot of the IVW estimates of the relationship between glycaemic exposures and anorexia nervosa. The estimates represent an odds ratio (OR) per unit increase in the exposure, with the error bars denoting the 95% confidence interval. The glycaemic exposures were as follows: fasting insulin, fasting glucose. glycated haemoglobin (HbA1c (all)), and a subset of glycaemic glycaeted haemoglobin lead SNPs. There was a significant protective effect of fasting insulin on anorexia nervosa after the application of multiple testing correction, and thus, that estimate is shaded orange. b Comparison of the IV-exposure association effect size for fasting insulin instrumental variables with, and without, phenotypic covariation for body mass index (BMI). The two panels plot the beta estimate of the 14 SNP-fasting insulin associations (error bars are 95% confidence interval) derived from the GWAS with or without adjustment for BMI. IV-estimates highlighted green were associated with fasting insulin at genome-wide significance (P < 5 × 10-8) irrespective of BMI adjustment (“both GW sig”), whilst red shaded SNP-exposure effects were only significant upon covariation for BMI. c Sensitivity analyses of BMI adjusted and unadjusted fasting insulin instrumental variables. We defined the instrumental variables for fasting insulin as follows: all IVs unadjusted for BMI, all IVs adjusted for BMI, IVs significant irrespective of BMI (stable IVs – estimates with and without BMI adjustment used). The forest plot denotes three MR estimators (IVW, weighted median, and weighted mode) using each of these IV subsets; each point represents the odds ratio for anorexia nervosa per natural log transformed pmol/L fasting insulin.

The scatterplots represent the IV effects on the exposure and outcome variables (black point), with the confidence intervals for both estimates denoted by the horizontal and vertical lines, respectively. Each coloured slope is indicative of the causal effect of a unit increase in the exposure on the outcome, estimated by the method in the legend utilised to shade the trendline – that is, inverse-variance weighted effect with multiplicative random effects (light blue), weighted median (light green), weighted mode (dark green), and MR-Egger (dark blue). The four panels correspond to a different exposure-outcome pair: (a) fasting insulin → anorexia nervosa, (b) fasting insulin → major depressive disorder, (c) anorexia nervosa → HbA1c, and (d) schizophrenia → fasting insulin.

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WRR designed the study with input from DMA, MPG, and MJC. DMA and WRR performed the analyses. DMA, WRR, and MJC wrote the first draft of the manuscript. All authors contributed to the interpretation of the results and the final manuscript. MPG and MJC supervised the project.

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Correspondence to Murray J. Cairns.

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Adams, D.M., Reay, W.R., Geaghan, M.P. et al. Investigation of glycaemic traits in psychiatric disorders using Mendelian randomisation revealed a causal relationship with anorexia nervosa. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00847-w

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