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. CLINICAL IMPLICATIONS: Further studies are needed to investigate whether the identified associations are effects of the metabolites itself or the biochemical pathway regulating the metabolites.

Two-sample Mendelian Randomization to evaluate the causal relationship between inflammatory arthritis and female-specific cancers.

BACKGROUND: There is evidence that inflammatory arthritis in the form of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and rheumatoid arthritis are both positively and negatively associated with certain female-specific cancers. However, the study results are very heterogeneous. METHODS: Based on up to 375,814 European women, we performed an iterative two-sample Mendelian randomization to assess causal effects of the occurrence of the inflammatory arthritis on the risk of female-specific cancer in form of breast, endometrial, and ovarian cancer sites as well as their subtypes. Evidence was strengthened by using similar exposures for plausibility or by replication with a subsequent meta-analysis. P-values were Bonferroni adjusted. RESULTS: Genetic liability to AS was associated with ovarian cancer (OR = 1.03; 95% CI: [1.01; 1.04]; [Formula: see text]=0.029) and liability to PsA with breast cancer (OR = 1.02; CI: [1.01; 1.04]; [Formula: see text]=0.002). Subgroup analyses revealed that the high-grade serous ovarian cancer (OR = 1.04; CI: [1.02; 1.06]; [Formula: see text]=0.015) and the ER- breast cancer (OR = 1.04; CI: [1.01; 1.07]; [Formula: see text]=0.118) appeared to drive the observed associations, respectively. No further associations were found between the remaining inflammatory arthritis phenotypes and female-specific cancers. CONCLUSIONS: This study suggests that AS is a risk factor for ovarian cancer, while PsA is linked to an increased breast cancer risk. These results are important for physicians caring women with inflammatory arthritis to advise their patients on cancer screening and preventive measures.

Stool and blood metabolomics in the metabolic syndrome: a cross-sectional study.

INTRODUCTION/OBJECTIVES: Changes in the stool metabolome have been poorly studied in the metabolic syndrome (MetS). Moreover, few studies have explored the relationship of stool metabolites with circulating metabolites. Here, we investigated the associations between stool and blood metabolites, the MetS and systemic inflammation. METHODS: We analyzed data from 1,370 participants of the KORA FF4 study (Germany). Metabolites were measured by Metabolon, Inc. (untargeted) in stool, and using the AbsoluteIDQ® p180 kit (targeted) in blood. Multiple linear regression models, adjusted for dietary pattern, age, sex, physical activity, smoking status and alcohol intake, were used to estimate the associations of metabolites with the MetS, its components and high-sensitivity C-reactive protein (hsCRP) levels. Partial correlation and Multi-Omics Factor Analysis (MOFA) were used to investigate the relationship between stool and blood metabolites. RESULTS: The MetS was significantly associated with 170 stool and 82 blood metabolites. The MetS components with the highest number of associations were triglyceride levels (stool) and HDL levels (blood). Additionally, 107 and 27 MetS-associated metabolites (in stool and blood, respectively) showed significant associations with hsCRP levels. We found low partial correlation coefficients between stool and blood metabolites. MOFA did not detect shared variation across the two datasets. CONCLUSIONS: The MetS, particularly dyslipidemia, is associated with multiple stool and blood metabolites that are also associated with systemic inflammation. Further studies are necessary to validate our findings and to characterize metabolic alterations in the MetS. Although our analyses point to weak correlations between stool and blood metabolites, additional studies using integrative approaches are warranted.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Plasma proteome association with coronary heart disease and carotid intima media thickness: results from the KORA F4 study.

BACKGROUND AND AIMS: Atherosclerosis is the main cause of stroke and coronary heart disease (CHD), both leading mortality causes worldwide. Proteomics, as a high-throughput method, could provide helpful insights into the pathological mechanisms underlying atherosclerosis. In this study, we characterized the associations of plasma protein levels with CHD and with carotid intima-media thickness (CIMT), as a surrogate measure of atherosclerosis. METHODS: The discovery phase included 1000 participants from the KORA F4 study, whose plasma protein levels were quantified using the aptamer-based SOMAscan proteomics platform. We evaluated the associations of plasma protein levels with CHD using logistic regression, and with CIMT using linear regression. For both outcomes we applied two models: an age-sex adjusted model, and a model additionally adjusted for body mass index, smoking status, physical activity, diabetes status, hypertension status, low density lipoprotein, high density lipoprotein, and triglyceride levels (fully-adjusted model). The replication phase included a matched case-control sample from the independent KORA F3 study, using ELISA-based measurements of galectin-4. Pathway analysis was performed with nominally associated proteins (p-value < 0.05) from the fully-adjusted model. RESULTS: In the KORA F4 sample, after Bonferroni correction, we found CHD to be associated with five proteins using the age-sex adjusted model: galectin-4 (LGALS4), renin (REN), cathepsin H (CTSH), and coagulation factors X and Xa (F10). The fully-adjusted model yielded only the positive association of galectin-4 (OR = 1.58, 95% CI = 1.30-1.93), which was successfully replicated in the KORA F3 sample (OR = 1.40, 95% CI = 1.09-1.88). For CIMT, we found four proteins to be associated using the age-sex adjusted model namely: cytoplasmic protein NCK1 (NCK1), insulin-like growth factor-binding protein 2 (IGFBP2), growth hormone receptor (GHR), and GDNF family receptor alpha-1 (GFRA1). After assessing the fully-adjusted model, only NCK1 remained significant (ß = 0.017, p-value = 1.39e-06). Upstream regulators of galectin-4 and NCK1 identified from pathway analysis were predicted to be involved in inflammation pathways. CONCLUSIONS: Our proteome-wide association study identified galectin-4 to be associated with CHD and NCK1 to be associated with CIMT. Inflammatory pathways underlying the identified associations highlight the importance of inflammation in the development and progression of CHD.

Can inflammatory plasma proteins predict Long COVID or Fatigue severity after SARS-CoV-2 infection?

OBJECTIVE: To investigate whether specific immune response plasma proteins can predict an elevated risk of developing Long COVID symptoms or fatigue severity after SARS-CoV-2 infection. METHODS: This study was based on 257 outpatients with test-confirmed SARS-CoV-2 infection between February 2020 and January 2021. At least 12 weeks after the acute infection, 92 plasma proteins were measured using the Olink Target 96 immune response panel (median time between acute infection and venous blood sampling was 38.8 [IQR: 24.0-48.0] weeks). The presence of Long COVID symptoms and fatigue severity was assessed 115.8 [92.5-118.6] weeks after the acute infection by a follow-up postal survey. Long COVID (yes/no) was defined as having one or more of the following symptoms: fatigue, shortness of breath, concentration or memory problems. The severity of fatigue was assessed using the Fatigue Assessment Scale (FAS). In multivariable-adjusted logistic and linear regression models the associations between each plasma protein (exposure) and Long COVID (yes/no) or severity of fatigue were investigated. RESULTS: Nine plasma proteins were significantly associated with Long COVID before, but not after adjusting for multiple testing (FDR-adjustment): DFFA, TRIM5, TRIM21, HEXIM1, SRPK2, PRDX5, PIK3AP1, IFNLR1 and HCLS1. Moreover, a total of 10 proteins were significantly associated with severity of fatigue before FDR-adjustment: SRPK2, ITGA6, CLEC4G, HEXIM1, PPP1R9B, PLXNA4, PRDX5, DAPP1, STC1 and HCLS1. Only SRPK2 and ITGA6 remained significantly associated after FDR-adjustment. CONCLUSIONS: This study demonstrates that certain immune response plasma proteins might play an important role in the pathophysiology of Long COVID and severity of fatigue after SARS-CoV-2 infection.

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, τ2, 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.

Association Between Acute Myocardial Infarction Symptoms and Short- and Long-term Mortality After the Event.

BACKGROUND: In this study, we investigated various acute myocardial infarction (AMI) symptoms and their associations with short-term (28 day) and long-term mortality. METHODS: The analysis was based on 5900 patients, aged 25 to 84 years, with first-time AMI recorded by the population-based Myocardial Infarction Registry Augsburg between 2010 and 2017. Median follow-up time was 3.8 years (interquartile range: 1.1-6.3). As part of a face-to-face interview, the presence (yes/no) of 11 most common AMI symptoms at the acute event was assessed. Using multivariable-adjusted logistic regression and Cox regression models, the association between various symptoms and all-cause mortality was investigated. P values of the regression models were false discovery rate adjusted. RESULTS: Pain in various body parts (chest pain, left and right shoulder/arm/hand, between shoulder blades), sweating, nausea/vomiting, dizziness and fear of death/feeling of annihilation were significantly associated with a decreased 28-day mortality after AMI. The pain symptoms and sweating were also significantly associated with a decreased long-term mortality. Shortness of breath was significantly associated with a higher long-term mortality. CONCLUSIONS: The absence of several symptoms, including typical chest discomfort (chest pain or retrosternal pressure/tightness), is associated with unfavourable outcomes after AMI. This finding has implications for patient management and public health measures designed to encourage appropriate and prompt medical consultation of patients with atypical AMI symptoms.

Do patients with diabetes with new onset acute myocardial infarction present with different symptoms than non-diabetic patients?

Background: The objective of this study was to investigate the differences in presenting symptoms between patients with and without diabetes being diagnosed with an acute myocardial infarction (AMI). Methods: A total of 5,900 patients with a first-time AMI were included into the analysis. All patients aged between 25 and 84 years were recorded by the population-based Myocardial Infarction Registry in Augsburg, Germany, between 2010 and 2017. The presence (yes/no) of 12 AMI typical symptoms during the acute event was assessed within the scope of a face-to-face interview. Multivariable adjusted logistic regression models were calculated to analyze the associations between presenting symptoms and diabetes mellitus in AMI patients. Results: Patients with diabetes had significantly less frequent typical pain symptoms, including typical chest pain. Also, other symptoms like sweating, vomiting/nausea, dizziness/vertigo and fear of death/feeling of annihilation occurred significantly more likely in non-diabetic patients. The only exception was the symptom of shortness of breath, which was found significantly more often in patients with diabetes. In multivariable-adjusted regression models, however, the observed effects were attenuated. In patients younger than 55 years, the associations between diabetes and various symptoms were mainly missing. Conclusions: Type 2 diabetes mellitus is a risk factor not only for the development of AMI, but is also associated with an adverse outcome after AMI. Atypical clinical presentation additionally complicates the diagnostic process. It is therefore essential for physicians to be aware of the more often atypical symptoms that diabetic AMI patients report.

Inflammation biomarkers in acute ischemic stroke according to different etiologies.

BACKGROUND: High throughput technologies provide new opportunities to further investigate the pathophysiology of ischemic strokes. The present cross-sectional study aimed to evaluate potential associations between the etiologic subtypes of ischemic stroke and blood-based proteins. METHODS: We investigated the associations between ischemic stroke subtypes and a panel of circulating inflammation biomarkers in 364 patients included in the Stroke Cohort Augsburg (SCHANA). Stroke etiologies were categorized according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Serum concentrations of 52 biomarkers were measured using the Bio-Plex Pro™ Human Cytokine Screening Panel, ICAM-1 set and VCAM-1 set, plus the Pro™ Human TH17 cytokine sCD40L set and IL31 set (all Bio-Rad, USA). Multivariable linear regression models were used to examine associations. Point estimates were calculated as the mean difference in σ -standardized cytokine levels on the log2 -scale. RESULTS: Stromal-cell-derived-factor 1 alpha (SDF-1a) showed significantly higher serum levels in cardioembolic compared with large vessel atherosclerotic stroke (ß = 0.48; 95% CI 0.22; 0.75; Padj = 0.036). Significantly lower levels of interleukin-6 (IL-6) (ß = -0.53; 95% CI -0.84; -0.23; Padj = 0.036) and macrophage migration inhibitory factor (MIF) (ß = -0.52; 95% CI -0.84; -0.21; Padj = 0.043) were found in the small vessel versus large vessel stroke subtype. CONCLUSIONS: Immune dysregulations observed in different stroke subtypes might help uncover pathophysiological mechanisms of the disease. Further studies are needed to validate identified biomarkers in diverse study populations before they can potentially be used in clinical practice to further improve stroke management and patient outcomes.

Causal effects of time-varying body size on selected autoimmune disorders: a life course Mendelian randomisation study.

BACKGROUND: Based on Barker's hypothesis, some studies investigated the associations between birth weight and several disorders. Apart from issues with statistical power and well-known shortcomings of the observational study design, there are no studies accounting for changes in weight-related body size over the life course regarding rheumatoid arthritis, psoriasis, psoriatic arthritis and multiple sclerosis. METHODS: Using genetic information of up to 806 834 participants, this study investigated the associations between time-varying weight-related body size from birth to adulthood and the mentioned autoimmune diseases. Performing Mendelian randomisation (MR), the radial inverse-variance weighted approach was used iteratively in primary analyses. Robustness of the results was confirmed in several sensitivity analyses. Potential time-dependent mediation mechanisms were identified through network-clustering and assessed using multivariable MR. RESULTS: Genetically predicted birth weight (fetal effect) was positively associated with rheumatoid arthritis (OR 1.44; 95% CI 1.17 to 1.77; Padj =0.005) but not with psoriasis, psoriatic arthritis or multiple sclerosis. This association was found to be mediated by body mass index (BMI) in adulthood (OR 1.45; 95% CI 1.14 to 1.84; Padj =0.019) rather than childhood. The direct effect of birth weight attenuated (OR 1.19; 95% CI 0.88 to 1.62); Padj =1) after adjustment for time-varying BMI. CONCLUSION: Increased birth weight appears to be a risk factor for later manifestation of rheumatoid arthritis due to both fetal genetic components and high BMI persisting into adulthood. Approaches to prevent and minimise the risk of rheumatoid arthritis could include preventing obesity in adults with high birth weight.

Fatigue, Depression and Health-Related Quality of Life in Patients with Post-Myocardial Infarction during the COVID-19 Pandemic: Results from the Augsburg Myocardial Infarction Registry.

The interplay between fatigue and depression and their association with health-related quality of life (HRQoL) after acute myocardial infarction (AMI) has received little attention during the COVID-19 pandemic. Therefore, this study evaluated the frequency of fatigue and depression in post-AMI patients during the COVID-19 pandemic and investigated the cross-sectional associations between fatigue, depression and HRQoL. METHODS: The analysis was based on population-based Myocardial Infarction Registry Augsburg data. All survivors of AMI between 1 June 2020 and 15 September 2021 were included (n = 882) and received a postal questionnaire containing questions about fatigue (Fatigue Assessment Scale), depression (Patient Health Questionnaire), and HRQoL (MacNew Heart Disease HRQoL questionnaire) on 17 November 2021. The questionnaire was returned by 592 patients (67.1%), and 574 participants could be included in the analysis. Multivariable linear regression models were performed to investigate the associations between fatigue and depression (both exposures) and HRQoL (outcome). RESULTS: Altogether, 273 (47.6%) participants met the criteria for the presence of fatigue, about 16% showed signs of moderate to severe depression. Both fatigue and depression were significantly associated with a decreased HRQoL (total score and emotional, social, and physical subscales; all p-values < 0.0001). In particular, a combined occurrence of fatigue and depression was associated with a significantly reduced HRQoL. CONCLUSIONS: It seems necessary to screen post-MI patients for the presence of fatigue and depression in clinical practice on a routine basis to provide them with adequate support and treatment and thus also to improve their HRQoL.

Understanding the causal relationships of attention-deficit/hyperactivity disorder with mental disorders and suicide attempt: a network Mendelian randomisation study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a lifespan neurodevelopmental condition resulting from complex interactions between genetic and environmental risk factors. There is evidence that ADHD is associated with other mental disorders, but it remains unclear whether and in what way a causal relationship exists. OBJECTIVE: To investigate the direct and indirect causal paths between ADHD and seven common mental disorders. METHODS: Two-sample network Mendelian randomisation analysis was performed to identify psychiatric disorders causally related to ADHD. Total and direct effects were estimated in an univariable and multivariable setting, respectively. Robustness of results was ensured in three ways: a range of pleiotropy-robust methods, an iterative approach identifying and excluding outliers, and use of up to two genome-wide association studies per outcome to replicate results and calculate subsequently pooled meta-estimates. RESULTS: Genetic liability to ADHD was independently associated with the risk of anorexia nervosa (OR 1.28 (95% CI 1.11 to 1.47); p=0.001). A bidirectional association was found with major depressive disorder (OR 1.09 (95% CI 1.03 to 1.15); p=0.003 in the forward direction and OR 1.76 (95% CI 1.50 to 2.06); p=4×10-12 in the reverse direction). Moreover, after adjustment for major depression disorder, a direct association with both suicide attempt (OR 1.30 (95% CI 1.16 to 1.547); p=2×10-5) and post-traumatic stress disorder (OR 1.18 (95% CI 1.05 to 1.33); p=0.007) was observed. There was no evidence of a relationship with anxiety, bipolar disorder or schizophrenia. CONCLUSIONS: This study suggests that ADHD is an independent risk factor for a number of common psychiatric disorders. CLINICAL IMPLICATIONS: The risk of comorbid psychiatric disorders in individuals with ADHD needs to be considered both in diagnosis and treatment.

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

Association between body fat distribution and B-lymphocyte subsets in peripheral blood.

BACKGROUND: Obesity is associated with chronic low-grade inflammation, which is underpinned by the presence of elevated levels of circulating proinflammatory cytokines in obese individuals. Due to the close relationship between adipose tissue and the immune system, it can be speculated that the accumulation of fat may influence the frequency and phenotype of lymphocyte populations. The aim of our study was to investigate whether body fat distribution is associated with B lymphocyte composition in peripheral blood. We examined the association between visceral (VAT) and total body fat (TBF) and the frequencies of B-cell subsets in 238 subjects over a period of up to one year using random intercept models. B lymphocyte subsets were determined by fluorescence-based flow cytometry. RESULTS: Inverse associations were found between body fat measurements and plasma blasts, memory B cells, and IgM-IgD- cells. VAT, but not TBF, was positively associated with naive CD19 cells. In our analyses, both VAT and TBF showed positive associations with IgD only B cells. CONCLUSIONS: In conclusion, body fat accumulation seems to be associated with a lower proportion of antibody-secreting plasma blasts and memory cells and an increasing amount of partially anergic, naive CD19 cells.

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 ([Formula: see text]; 95% CI: (-0.10; -0.02); [Formula: see text]). 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.

Baseline fibroblast growth factor 23 is associated with long-term mortality in ST-elevation myocardial infarction-results from the augsburg myocardial infarction registry.

Background: The aim of this study was to investigate the association between inflammatory plasma protein concentrations and long-term mortality in patients with ST-elevation myocardial infarction (STEMI). Methods: For 343 STEMI patients recorded between 2009 and 2013 by the population-based Myocardial Infarction Registry Augsburg, 92 inflammatory plasma proteins were measured at the index event using the OLINK inflammation panel. In multivariable-adjusted Cox regression models, the association between each plasma protein and all-cause long-term mortality was investigated. Median follow-up time was 7.6 (IQR: 2.4) years. For plasma protein that showed a strong association with long-term mortality, a 5-year survival ROC analysis was performed. Results: One plasma protein, namely Fibroblast Growth Factor 23 (FGF-23), was particularly well associated with long-term mortality in the multivariable-adjusted Cox model with an FDR-adjusted p-value of <0.001 and a Hazard Ratio (HR) of 1.57 [95% CI: 1.29-1.91]. In the 5-years ROC analysis, an AUC of 0.6903 [95% CI: 0.594-0.781] was estimated for FGF-23. All other plasma protein didnt show strong associations, each marker with FDR-adjusted p-values >0.05 in the multivariable-adjusted Cox models. Conclusions: FGF-23 is independently associated with long-term mortality after STEMI and might play an important role in the response to myocardial injury. The results suggest FGF-23 to be a useful marker in the long-term treatment of STEMI patients and a potential target for drug development.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Associations between serum cholesterol and immunophenotypical characteristics of circulatory B cells and Tregs.

Blood lipids play a major role in the manifestation of cardiovascular diseases. Recent research suggested that there are connections between cholesterol levels and immunological alterations. We investigated whether there is an association between serum cholesterol levels (total, HDL, and LDL) and immune cells (B cell and regulatory T cells [Tregs]). The analysis was based on data from 231 participants of the MEGA study in Augsburg, Germany, recruited between 2018 and 2021. Most participants were examined two different times within a period of 9 months. At every visit, fasting venous blood samples were taken. Immune cells were analyzed immediately afterward using flow cytometry. Using multivariable-adjusted linear regression models, the associations between blood cholesterol concentrations and the relative quantity of several B-cell and Treg subsets were analyzed. We found that particularly HDL cholesterol concentrations were significantly associated to some immune cell subpopulations: HDL cholesterol showed significant positive associations with the relative frequency of CD25++ Tregs (as proportion of all CD4+CD25++ T cells) and conventional Tregs (defined as the proportion of CD25+CD127- cells on all CD45RA-CD4+ T cells). Regarding B cells, HDL cholesterol values were inversely associated with the cell surface expression of IgD and with naïve B cells (CD27-IgD+ B cells). In conclusion, HDL cholesterol levels were associated with modifications in the composition of B-cell and Treg subsets demonstrating an important interconnection between lipid metabolism and immune system. Knowledge about this association might be crucial for a deeper and more comprehensive understanding of the pathophysiology of atherosclerosis.