Mediation-adjusted multivariable Mendelian randomisation study identified novel metabolites related to mental health

Background: From the pathway perspective, metabolites have the potential to improve knowledge about the aetiology of psychiatric diseases. Previous studies suggested a link between specific blood metabolites and mental disorders, but some Mendelian randomisation (MR) studies in particular are insufficient for various reasons. Objective: This study focused on bias assessment due to interdependencies between metabolites and psychiatric mediation effects. Methods: In a multistep framework containing network and multivariable MR, direct effects of 21 mutually adjusted metabolites on 8 psychiatric disorders were estimated based on summary statistics of genome-wide association studies from multiple resources. Robust inverse-variance weighted models were used in primary analyses. Several sensitivity analyses were performed to assess different patterns of pleiotropy and weak instrument bias. Estimates for the same phenotypes from different resources were pooled using fixed effect meta-analysis models. Findings: After adjusting for mediation effects, genetically predicted metabolite levels of six metabolites of lipid, amino acid and cofactors pathways were directly associated with overall six mental disorders (attention-deficit/hyperactivity disorder, bipolar disorder, anorexia nervosa, depression, post-traumatic stress disorder and schizophrenia). Point estimates ranged from −0.45 (95% CI −0.67; −0.24, p=1.0×104) to 1.78 (95% CI 0.85; 2.71, p=0.006). No associations were found with anxiety and suicide attempt. Conclusions: This study provides insights into new metabolic pathways that seems to be causally related to certain mental disorders

Causal link between thyroid function and schizophrenia: a two-sample Mendelian randomization study

Schizophrenia is a chronic psychiatric disorder with inconsistent behavioral and cognitive abnormalities with profound effects on the individual and the society. Individuals with schizophrenia have altered thyroid function, but results from observational studies are conflicting. To date, it remains unclear whether and in which direction there is a causal relationship between thyroid function and schizophrenia. To investigate causal paths, a bidirectional two-sample Mendelian randomization (MR) study was conducted using summary statistics from genome-wide association studies including up to 330,132 Europeans. Thyroid function was described by the normal-range thyroid-stimulating hormone (TSH) and free thyroxine levels as well as an increased and decreased TSH status. The iterative radial inverse-variance weighted approach with modified second order weights was used as the main method. Based on a discovery and replication sample for schizophrenia, pooled effect estimates were derived using a fixed-effect meta-analysis. Robustness of results was assessed using both a range of pleiotropy robust methods and a network analysis that clustered genetic instruments potentially responsible for horizontal pleiotropy. Genetic liability for hypothyroidism was inversely associated with schizophrenia (β=−0.06; 95% CI: (-0.10; -0.02); P=0.004). No notable associations were observed between other thyroid parameters and schizophrenia. Furthermore, no associations could be detected in the reverse direction. Our results suggest that an elevated level of TSH reduce the risk for schizophrenia. The role of thyroid function and the hypothalamic-pituitary-thyroid axis in the development of schizophrenia should be subject of further research

Asthma and the risk of gastrointestinal disorders: a Mendelian randomization study

BACKGROUND: The question of whether asthma is causally related to gastrointestinal disorders remained unanswered so far. Thus, this study investigated whether there is such a relation and whether the time of onset of asthma plays a role in the occurrence of the following gastrointestinal disorders: peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD) including the distinction between Crohn’s disease (CD) and ulcerative colitis (UC). METHODS: Using summary data of genome-wide association studies (GWASs), we ran Mendelian randomization analyses based on up to 456,327 European participants. Outlier assessment, a series of sensitivity analyses and validation of IBD results in a second GWAS were performed to confirm the results. RESULTS: Presented ORs represent the average change in the outcome per 2.72-fold increase in the prevalence of the exposure. Genetically predicted childhood-onset asthma was positively associated with PUD, GORD, and IBS with similar odds ratios near 1.003 and adjusted P-values from 0.007 (GORD) to 0.047 (PUD). Furthermore, it was inversely related to IBD (OR = 0.992, 95% CI: 0.986, 0.998, adjusted P = 0.023) and suggestively associated with its UC subtype (OR = 0.990, 95% CI: 0.982, 0.998, adjusted P = 0.059). There were no associations between genetically predicted adult-onset asthma and the mentioned gastrointestinal disorders. CONCLUSIONS: This study provides evidence that the presence of asthma onset in childhood increases the risk for GORD, PUD, and IBS but decreases the risk for IBD in adults. The lower risk for IBD may be attributed to a lower risk primarily for UC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02283-7

Autoimmune diseases and female-specific cancer risk: a systematic review and meta-analysis

Objectives Among the over 80 different autoimmune diseases, psoriasis (PsO), rheumatoid arthritis (RA), and ankylosing spondylitis (AS) are common representatives. Previous studies indicated a potential link with cancer risk, but suffered often from low statistical power. Thus, we aimed to synthesize the evidence and quantify the association to different female-specific cancer sites. Methods The systematic review was performed according to PRISMA guidelines. A search string was developed for the databases PubMed, Web of Science, Cochrane Library and Embase. Results were screened independently by two investigators and the risk of bias was assessed using the ROBINS-E tool. Meta-analyses were performed using inverse variance weighted random-effects models. Statistical between-study heterogeneity was quantified by calculating Cochran's Q, , and Higgins' I2 statistics. Sources of heterogeneity were analyzed and adjusted for within an intensive bias assessment in the form of meta-regression, outlier, influential, and subgroup analyses. A range of methods were used to test and adjust for publication bias. Results Of 10,096 records that were originally identified by the search strategy, 45 were included in the meta-analyses. RA was inversely associated with both breast and uterine cancer occurrence, while PsO was associated with a higher breast cancer risk. Outlier-adjusted estimates confirmed these findings. Bias assessment revealed differences in geographic regions, particularly in RA patients, with higher estimates among Asian studies. An additional analysis revealed no association between psoriatic arthritis and breast cancer. Conclusions RA seems to reduce the risk of breast and uterine cancers, while PsO appears to increase breast cancer risk. Further large studies are required to investigate potential therapy-effects and detailed biological mechanisms