Metabolomics Profile in Depression:A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls

BACKGROUND: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons. METHODS: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses. RESULTS: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms. CONCLUSIONS: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity

Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels

This article is free to read on the publisher's website Metabolites are small molecules involved in cellular metabolism, which can be detected in biological samples using metabolomic techniques. Here we present the results of genome-wide association and meta-analyses for variation in the blood serum levels of 129 metabolites as measured by the Biocrates metabolomic platform. In a discovery sample of 7,478 individuals of European descent, we find 4,068 genome- and metabolome-wide significant (Z-test, P<1.09 × 10−9) associations between single-nucleotide polymorphisms (SNPs) and metabolites, involving 59 independent SNPs and 85 metabolites. Five of the fifty-nine independent SNPs are new for serum metabolite levels, and were followed-up for replication in an independent sample (N=1,182). The novel SNPs are located in or near genes encoding metabolite transporter proteins or enzymes (SLC22A16, ARG1, AGPS and ACSL1) that have demonstrated biomedical or pharmaceutical importance. The further characterization of genetic influences on metabolic phenotypes is important for progress in biological and medical research

Interexaminer Agreement and Reliability of an Internationally Endorsed Screening Framework for Cervical Vascular Risks Following Manual Therapy and Exercise:The Go4Safe Project

Objective: Clinicians are recommended to use the clinical reasoning framework developed by the International Federation of Orthopaedic Manipulative Physical Therapists (IFOMPT) to provide guidance regarding assessment of the cervical spine and potential for cervical artery dysfunction prior to manual therapy and exercise. However, the interexaminer agreement and reliability of this framework is unknown. This study aimed to estimate the interexaminer agreement and reliability of the IFOMPT framework among physical therapists in primary care. Methods: Ninety-six patients who consulted a physical therapist for neck pain or headache were included in the study. Each patient was tested independently by 2 physical therapists, from a group of 17 physical therapists (10 pairs) across The Netherlands. Patients and examiners were blinded to the test results. The overall interexaminer agreement, specific agreement per risk category (high-, intermediate-, and low-risk), and interexaminer reliability (weighted κ) were calculated. Results: Overall agreement was 71% (specific agreement in high-risk category = 63%; specific agreement in intermediate-risk category = 38%; specific agreement in low-risk category = 84%). Overall reliability was moderate (weighted κ = 0.39; 95% CI = 0.21-0.57) and varied considerably between pairs of physical therapists (κ = 0.14-1.00). Conclusion: The IFOMPT framework showed an insufficient interexaminer agreement and fair interexaminer reliability among physical therapists when screening the increased risks for vascular complications following manual therapy and exercise prior to treatment. Impact: The IFOMPT framework contributes to the safety of manual therapy and exercise. It is widely adopted in clinical practice and educational programs, but the measurement properties are unknown. This project describes the agreement and reliability of the IFOMPT framework

Genetics and Not Shared Environment Explains Familial Resemblance in Adult Metabolomics Data

Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term 'metabolomics' refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2x)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted

An endometrial histomorphometric study of CD56+ natural killer cells in women with unexplained infertility

BACKGROUND. The number of peripheral blood and endometrial natural killer cells varies greatly during implantation and the first trimester of pregnancy and is thought to play a role in the maintenance of a healthy pregnancy. However, the role of endometrial CD56+ natural killer (NK) cells as an immunological mechanism in unexplained infertility is yet unknown. OBJECTIVES. The study aimed to enumerate the concentrations of CD56+ NK cells in endometrial samples, and to statistically compare these numbers between fertile and infertile women. METHODS. A histomorphometric analysis was conducted using haematoxylin and eosin staining and an immunohistochemical approach was used for quantifying cell numbers. RESULTS. Fifty samples were collected in equal parts between a study group of infertile female subjects (mean (standard deviation) age 35 (4), range 26 - 42 years) and a control group of multiparous fertile individuals (mean (SD) age 43.4 (6.3), range 30 - 55). The mean number of CD56+ NK cells present at different depths for both the study and control groups did not differ significantly. Age and group (study or control) were not significantly related to the mean number of CD56+ NK cells. However, for the late secretory phase the mean number of CD56+ NK cells was significantly higher than for the early phase. CONCLUSION. Our findings could not identify a statistically significant correlation between the number of CD56+ NK cells and infertility.Discovery Foundation Research Awardshttp://sajog.org.za/index.php/SAJOGhttp://www.journals.co.za/content/journalam2017Anatomical PathologyAnatomyHaematologyImmunologyStatistic

Heritability estimates for 361 blood metabolites across 40 genome-wide association studies

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2 total), and the proportion of heritability captured by known metabolite loci (h2 Metabolite-hits) for 309 lipids and 52 organic acids. Our study reveals significant differences in h2 Metabolite-hits among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation have higher h2 Metabolite-hits estimates than phosphatidylcholines with low degrees of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes

Highly Regio- and Stereoselective Diels-Alder Cycloadditions via Two-Step and Multicomponent Reactions Promoted by Infrared Irradiation under Solvent-Free Conditions

Infrared irradiation promoted the Diels-Alder cycloadditions of exo-2-oxazolidinone dienes 1–3 with the Knoevenagel adducts 4–6, as dienophiles, leading to the synthesis of new 3,5-diphenyltetrahydrobenzo[d]oxazol-2-one derivatives (7, 9, 11 and 13–17), under solvent-free conditions. These cycloadditions were performed with good regio- and stereoselectivity, favoring the para-endo cycloadducts. We also evaluated the one-pot three-component reaction of active methylene compounds 20, benzaldehydes 21 and exo-2-oxazolidinone diene 2 under the same reaction conditions. A cascade Knoevenagel condensation/Diels-Alder cycloaddition reaction was observed, resulting in the final adducts 13–16 in similar yields. These procedures are environmentally benign, because no solvent and no catalyst were employed in these processes. The regioselectivity of these reactions was rationalized by Frontier Molecular Orbital (FMO) calculations

Metabolomics Profile in Depression:A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls

Background: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons. Methods: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses. Results: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q <.05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms. Conclusions: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity

Genetic Relationship between Schizophrenia and Nicotine Dependence

It is well known that most schizophrenia patients smoke cigarettes. There are different hypotheses postulating the underlying mechanisms of this comorbidity. We used summary statistics from large meta-analyses of plasma cotinine concentration (COT), Fagerström test for nicotine dependence (FTND) and schizophrenia to examine the genetic relationship between these traits. We found that schizophrenia risk scores calculated at P-value thresholds of 5 × 10−3 and larger predicted FTND and cigarettes smoked per day (CPD), suggesting that genes most significantly associated with schizophrenia were not associated with FTND/CPD, consistent with the self-medication hypothesis. The COT risk scores predicted schizophrenia diagnosis at P-values of 5 × 10−3 and smaller, implying that genes most significantly associated with COT were associated with schizophrenia. These results implicated that schizophrenia and FTND/CPD/COT shared some genetic liability. Based on this shared liability, we identified multiple long non-coding RNAs and RNA binding protein genes (DA376252, BX089737, LOC101927273, LINC01029, LOC101928622, HY157071, DA902558, RBFOX1 and TINCR), protein modification genes (MANBA, UBE2D3, and RANGAP1) and energy production genes (XYLB, MTRF1 and ENOX1) that were associated with both conditions. Further analyses revealed that these shared genes were enriched in calcium signaling, long-term potentiation and neuroactive ligand-receptor interaction pathways that played a critical role in cognitive functions and neuronal plasticity.</p