Causal associations between female reproductive behaviors and psychiatric disorders: a lifecourse Mendelian randomization study.

BACKGROUND: The timings of reproductive life events have been examined to be associated with various psychiatric disorders. However, studies have not considered the causal pathways from reproductive behaviors to different psychiatric disorders. This study aimed to investigate the nature of the relationships between five reproductive behaviors and twelve psychiatric disorders. METHODS: Firstly, we calculated genetic correlations between reproductive factors and psychiatric disorders. Then two-sample Mendelian randomization (MR) was conducted to estimate the causal associations among five reproductive behaviors, and these reproductive behaviors on twelve psychiatric disorders, using genome-wide association study (GWAS) summary data from genetic consortia. Multivariable MR was then applied to evaluate the direct effect of reproductive behaviors on these psychiatric disorders whilst accounting for other reproductive factors at different life periods. RESULTS: Univariable MR analyses provide evidence that age at menarche, age at first sexual intercourse and age at first birth have effects on one (depression), seven (anxiety disorder, ADHD, bipolar disorder, bipolar disorder II, depression, PTSD and schizophrenia) and three psychiatric disorders (ADHD, depression and PTSD) (based on p<7.14×10-4), respectively. However, after performing multivariable MR, only age at first sexual intercourse has direct effects on five psychiatric disorders (Depression, Attention deficit or hyperactivity disorder, Bipolar disorder, Posttraumatic stress disorder and schizophrenia) when accounting for other reproductive behaviors with significant effects in univariable analyses. CONCLUSION: Our findings suggest that reproductive behaviors predominantly exert their detrimental effects on psychiatric disorders and age at first sexual intercourse has direct effects on psychiatric disorders.

Association between dietary habits and the risk of migraine: a Mendelian randomization study.

Objective: The important contribution of dietary triggers to migraine pathogenesis has been recognized. However, the potential causal roles of many dietary habits on the risk of migraine in the whole population are still under debate. The objective of this study was to determine the potential causal association between dietary habits and the risk of migraine (and its subtypes) development, as well as the possible mediator roles of migraine risk factors. Methods: Based on summary statistics from large-scale genome-wide association studies, we conducted two-sample Mendelian randomization (MR) and bidirectional MR to investigate the potential causal associations between 83 dietary habits and migraine and its subtypes, and network MR was performed to explore the possible mediator roles of 8 migraine risk factors. Results: After correcting for multiple testing, we found evidence for associations of genetically predicted coffee, cheese, oily fish, alcohol (red wine), raw vegetables, muesli, and wholemeal/wholegrain bread intake with decreased risk of migraine, those odds ratios ranged from 0.78 (95% CI: 0.63-0.95) for overall cheese intake to 0.61 (95% CI: 0.47-0.80) for drinks usually with meals among current drinkers (yes + it varies vs. no); while white bread, cornflakes/frosties, and poultry intake were positively associated with the risk of migraine. Additionally, genetic liability to white bread, wholemeal/wholegrain bread, muesli, alcohol (red wine), cheese, and oily fish intake were associated with a higher risk of insomnia and (or) major depression disorder (MDD), each of them may act as a mediator in the pathway from several dietary habits to migraine. Finally, we found evidence of a negative association between genetically predicted migraine and drinking types, and positive association between migraine and cups of tea per day. Significance: Our study provides evidence about association between dietary habits and the risk of migraine and demonstrates that some associations are partly mediated through one or both insomnia and MDD. These results provide new insights for further nutritional interventions for migraine prevention.

Comparative efficacy and safety of glucose-lowering drugs in children and adolescents with type 2 diabetes: A systematic review and network meta-analysis.

Objective: Type 2 diabetes is more common in adults, but is becoming the major concern in children and adolescent recently. This study aimed to provide additional pharmaceutical management for children and adolescents with type 2 diabetes by assessing the efficacy and safety of several glucose-lowering drugs. Methods: Searches were performed in PubMed, Medline, Ovid, Cochrane Controlled Register of Trials (CENTRAL), and ClinicalTrials.gov that reported the efficacy and safety of drugs for children and adolescents with type 2 diabetes. Pooled effects were calculated by frequentist fixed effects network meta-analyses and additive network meta-analyses. Results: A total of 12 trials assessing eight glucose-lowering drugs were included, which compose of seven trials with monotherapy and five trials with combination therapies. Network meta-analysis results showed compared to placebo, saxagliptin+metformin (mean difference (MD) -1.91% [-2.85%, -0.97%]), liraglutide+metformin (MD -1.45% [-1.65%, -1.26%]), and liraglutide (MD -0.90% [-1.35%, -0.45%]) were the top 3 drugs that significantly reduced hemoglobin A1c (HbA1c). Sitagliptin+metformin, dapagliflozin, exenatide-2mcg, linagliptin-5mg, metformin, exenatide-5/10mcg, glimepiride, and sitagliptin also showed significant reduction in HbA1c. There were no significant differences between treatments in the incidence of adverse events, except that liraglutide+metformin had significant adverse effect such as abdominal pain. In addition, dapagliflozin, sitagliptin+metformin, and saxagliptin+metformin showed better efficacy compared with FDA-approved drugs. Conclusions: The top 10 treatments of type 2 diabetes in children and adolescents aged 10-17 years were saxagliptin+metformin, liraglutide+metformin, liraglutide, dapagliflozin, exenatide-2 mcg, sitagliptin+metformin, linagliptin-5 mg, linagliptin-1 mg, metformin, and exenatide-5/10 mcg. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=284897, identifier CRD42021284897.