Assessing the Role of Cortisol in Anxiety, Major Depression, and Neuroticism: A Mendelian Randomization Study Using SERPINA6/SERPINA1 Variants.

Background: Previous evidence informed by the toxic stress model suggests that higher cortisol causes anxiety and major depression, but clinical success is lacking. To clarify the role of cortisol, we used Mendelian randomization to estimate its associations with anxiety, major depression, and neuroticism, leveraging the largest available genome-wide association studies including from the Psychiatric Genomics Consortium, the UK Biobank, and FinnGen. Methods: After meta-analyzing 2 genome-wide association studies on morning plasma cortisol (n = 32,981), we selected single nucleotide polymorphisms (SNPs) at p < 5 × 10-8 and r2 < 0.3 in the SERPINA6/SERPINA1 gene region encoding proteins that influence cortisol bioavailability. We applied these SNPs to summary genetic associations with the outcomes considered (n = 17,310-449,484), and systolic blood pressure as a positive outcome, using inverse-variance weighted meta-analysis accounting for correlation. Sensitivity analyses addressing SNP correlation and confounding by childhood maltreatment and follow-up analyses using only SNPs that colocalized with SERPINA6 expression were conducted. Results: Cortisol was associated with anxiety (pooled odds ratio [OR] 1.16 per cortisol z score; 95% CI, 1.04 to 1.31), but not major depression (pooled OR 1.02, 95% CI, 0.95 to 1.10) or neuroticism (ß -0.025; 95% CI, -0.071 to 0.022). Sensitivity analyses yielded similar estimates. Cortisol was positively associated with systolic blood pressure, as expected. Using rs9989237 and rs2736898, selected using colocalization, cortisol was associated with anxiety in the UK Biobank (OR 1.32; 95% CI, 1.01 to 1.74) but not with major depression in FinnGen (OR 1.14; 95% CI, 0.95 to 1.37). Conclusions: Cortisol was associated with anxiety and may be a potential target for prevention. Other targets may be more relevant to major depression and neuroticism.

Previous observational studies and randomized controlled trials remain inconclusive about whether cortisol causes mental disorders. In this Mendelian randomization study, using genetic variants from the SERPINA6/SERPINA1 gene region as instrumental variables for cortisol to minimize bias from confounding, we found that morning plasma cortisol was positively associated with anxiety but not major depression or neuroticism. From a practical perspective, these findings provide supporting evidence that lowering cortisol may reduce the risk of anxiety but not depression.

Maternal respiratory health and intrauterine exposure-driven birthweight: a two-sample Mendelian randomization study.

BACKGROUND: Observationally, poorer maternal respiratory health is associated with poorer birth outcomes, possibly confounded by socioeconomic position and other maternal attributes. We used multivariable Mendelian randomization (MR) to obtain unconfounded estimates of effect of maternal lung function on birthweight, independent of maternal height. METHODS: Single nucleotide polymorphisms (SNPs) for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in women were obtained from publicly available summary statistics from the UK Biobank. SNPs for asthma were obtained from the Trans-National Asthma Genetic consortium. SNPs for height in women were obtained from the Genetic Investigation of Anthropometric Traits consortium and the genetic estimates were obtained the UK Biobank. The genetic associations with maternally-driven birthweight were obtained from the Early Growth Genetics consortium. Multivariable MR estimates were obtained using inverse variance weighting with multivariable MR-Egger as sensitivity analysis. RESULTS: Maternal lung capacity, as indicated by FVC, was positively associated with maternally-driven birthweight (0.08 per standard deviation, 95% confidence interval 0.01 to 0.15) independent of maternal height, whereas no clear such associations were shown for maternal airway function, indicated by FEV1 and peak expiratory flow, or for asthma, on maternally-driven birthweight. Similar findings were shown using MR-Egger. CONCLUSIONS: These findings suggest that maternal lung function, especially lung capacity independent of maternal height, is directly associated with maternally-driven birthweight, and highlights the importance of maternal respiratory health in fetal growth.

Timing of Pubertal Development and Midlife Blood Pressure in Men and Women: A Mendelian Randomization Study.

INTRODUCTION: Observational studies suggest earlier puberty is associated with higher adulthood blood pressure (BP), but these findings have not been replicated using Mendelian randomization (MR). We examined this question sex-specifically using larger genome-wide association studies (GWAS) with more extensive measures of pubertal timing. METHODS: We obtained genetic instruments proxying pubertal maturation (age at menarche [AAM] or voice breaking [AVB]) from the largest published GWAS. We applied them to summary sex-specific genetic associations with systolic and diastolic BP z-scores, and self-reported hypertension in women (n = 194 174) and men (n = 167 020) from the UK Biobank, using inverse-variance weighted meta-analysis. We conducted sensitivity analyses using other MR methods, including multivariable MR adjusted for childhood obesity proxied by body mass index (BMI). We used late pubertal growth as a validation outcome. RESULTS: AAM (beta per 1-year later = -0.030 [95% confidence interval, -0.055 to -0.005] and AVB (beta -0.058 [95% CI, -0.100 to -0.015]) were inversely associated with systolic BP independent of childhood BMI, as were diastolic BP (-0.035 [95% CI, -0.060 to -0.009] for AAM and -0.046 [95% CI, -0.089 to -0.004] for AVB) and self-reported hypertension (odds ratio 0.89 [95% CI, 0.84-0.95] for AAM and 0.87 [95% CI, 0.79-0.96] for AVB). AAM and AVB were positively associated with late pubertal growth, as expected. The results were robust to sensitivity analysis using other MR methods. CONCLUSION: Timing of pubertal maturation was associated with adulthood BP independent of childhood BMI, highlighting the role of pubertal maturation timing in midlife BP.

Blood pressure and risk of cancer: a Mendelian randomization study.

BACKGROUND: Previous large observational cohort studies showed higher blood pressure (BP) positively associated with cancer. We used Mendelian randomization (MR) to obtain less confounded estimates of BP on total and site-specific cancers. METHODS: We applied replicated genetic instruments for systolic and diastolic BP to summary genetic associations with total cancer (37387 cases, 367856 non-cases) from the UK Biobank, and 17 site-specific cancers (663-17881 cases) from a meta-analysis of the UK Biobank and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging. We used inverse-variance weighting with multiplicative random effects as the main analysis, and sensitivity analyses including the weighted median, MR-Egger and multivariable MR adjusted for body mass index and for smoking. For validation, we included breast (Breast Cancer Association Consortium: 133384 cases, 113789 non-cases), prostate (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium: 79194 cases, 61112 non-cases) and lung (International Lung and Cancer Consortium: 10246 cases, 38295 non-cases) cancer from large consortia. We used asthma as a negative control outcome. RESULTS: Systolic and diastolic BP were unrelated to total cancer (OR 0.98 per standard deviation higher [95% confidence interval (CI) 0.89, 1.07] and OR 1.00 [95% CI 0.92, 1.08]) and to site-specific cancers after accounting for multiple testing, with consistent findings from consortia. BP was nominally associated with melanoma and possibly kidney cancer, and as expected, not associated with asthma. Sensitivity analyses using other MR methods gave similar results. CONCLUSIONS: In contrast to previous observational evidence, BP does not appear to be a risk factor for cancer, although an effect on melanoma and kidney cancer cannot be excluded. Other targets for cancer prevention might be more relevant.

The total and direct effects of systolic and diastolic blood pressure on cardiovascular disease and longevity using Mendelian randomisation.

The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guidelines lowered the hypertension threshold to ≥ 130/80 mmHg, but the role of diastolic BP remains contested. This two-sample mendelian randomisation study used replicated genetic variants predicting systolic and diastolic BP applied to the UK Biobank and large genetic consortia, including of cardiovascular diseases and parental lifespan, to obtain total and direct effects. Systolic and diastolic BP had positive total effects on CVD (odds ratio (OR) per standard deviation 2.15, 95% confidence interval (CI) 1.95, 2.37 and OR 1.91, 95% CI 1.73, 2.11, respectively). Direct effects were similar for systolic BP (OR 1.83, 95% CI 1.48, 2.25) but completely attenuated for diastolic BP (1.18, 95% CI 0.97, 1.44), although diastolic BP was associated with coronary artery disease (OR 1.24, 95% CI 1.03, 1.50). Systolic and diastolic BP had similarly negative total (- 0.20 parental attained age z-score, 95% CI - 0.22, - 0.17 and - 0.17, 95% CI - 0.20, - 0.15, respectively) and direct negative effects on longevity. Our findings suggest systolic BP has larger direct effects than diastolic BP on CVD, but both have negative effects (total and direct) on longevity, supporting the 2017 ACC/AHA guidelines lowering both BP targets.