Association of Cortisol Levels With Neuropsychiatric Functions: A Mendelian Randomization Analysis

Abstract

Aim: The conflicting evidence as to whether a real association exists between cortisol levels and depression lends support to adopting a Mendelian randomization approach to investigate whether cortisol levels have a causal effect with depression. Methods: Single nucleotide polymorphisms (SNPs) associated with serum morning plasma cortisol level and salivary cortisol level from CORNET consortium (12,597 participants) were proposed as instrumental variables. The primary outcome was depression, and the secondary outcomes were neuroticism and cognitive performance. Summary-level statistics were extracted from the Social Science Genetic Association Consortium including the United Kingdom Biobank cohort (105,739 subjects). Multiple analysis methods (inverse-variance weighted method, max likelihood method, weighted median estimator, model-based estimation, heterogeneity-penalized method, and MR-Egger regression) were applied to test the stability of the summary causal estimate. Results: Weighted median analysis estimated that the effect of serum morning cortisol on depression score was 0.027 per standard deviation increase of cortisol (95% CI, 0.000-0.054; p = 0.043). Other sensitivity analysis suggested similar results suggesting the result was robust. No evidence of pleiotropy (MR-Egger intercept, -0.002; p = 0.739) was observed. The effect of serum cortisol on neuroticism was 0.030 (95% CI, 0.008-0.052; p = 0.006) by weighted median estimator. None of the methods observed the effect of serum cortisol level on cognitive function. As for the effect of salivary cortisol level, no method obtained a p-value lower than 0.05 in any of the outcomes. Conclusion: Mendelian randomization analysis provided evidence that a genetic predisposition to higher serum morning cortisol level was associated with increased depression score.

Keywords: Cushing's syndrome; cortisol; depression; neuroendocrinology; single nucleotide polymorphisms.

Figure 1

Causal diagram and three assumptions in mendelian randomization.

Figure 2

Causal effect of serum morning cortisol level on neuropsychiatric functions. X-axis represents the effect of per standard deviation of serum cortisol increase on the neuropsychiatric outcomes. Boxes represent point estimations of the effect with the 95% confidence interval. Different colors represent different statistical methods.

Figure 3

Sensitivity plot of genetic association with exposure vs. with outcome using multiple methods. Points represent SNPs. There was no evidence of pleiotropy represent by the intercept of MR-Egger (−0.002, p = 0.739).

Figure 4

Causal effect of salivary cortisol level on neuropsychiatric functions. X-axis represents the effect of per standard deviation of salivary cortisol increase on the neuropsychiatric outcomes. Boxes represent point estimations of the effect with the 95% confidence interval. Different colors represent different statistical methods.