Metabotype identification via fasting and postprandial metabolomics and its association with type 2 diabetes incidence.

Background: Metabotypes represent distinct metabolic profiles that groups of individuals share, facilitating disease risk stratification. We aimed to apply metabolomics to identify metabotypes in different prandial states and examine its associations with type 2 diabetes mellitus (T2DM) risk.

Methods: Using fasting and postprandial metabolomic data from the Netherlands Epidemiology of Obesity (NEO) study (N = 5320), we applied -means clustering to identify individual’s metabotypes for three prandial states (fasting, postprandial [150 min after meal], and postprandial minus fasting, i.

Non-linear Mendelian randomization: evaluation of effect modification in the residual and doubly-ranked methods with simulated and empirical examples.

Non-linear Mendelian randomisation (NLMR) is a relatively recently developed approach to estimate the causal effect of an exposure on an outcome where this is expected to be non-linear. Two commonly used techniques-based on stratifying the exposure and performing Mendelian randomisation (MR) within each strata-are the residual and doubly-ranked methods. The residual method is known to be biased in the presence of genetic effect heterogeneity-where the effect of the genotype on the exposure varies between individuals.

Non-linear Mendelian randomization: detection of biases using negative controls with a focus on BMI, Vitamin D and LDL cholesterol.

Mendelian randomisation (MR) is an established technique in epidemiological investigation, using the principle of random allocation of genetic variants at conception to estimate the causal linear effect of an exposure on an outcome. Extensions to this technique include non-linear approaches that allow for differential effects of the exposure on the outcome depending on the level of the exposure. A widely used non-linear method is the residual approach, which estimates the causal effect within different strata of the non-genetically predicted exposure (i.

The association between body mass index and metabolite response to a liquid mixed meal challenge: a Mendelian randomization study.

Background: Metabolite abundance is a dynamic trait that varies in response to environmental stimuli and phenotypic traits, such as food consumption and body mass index (BMI, kg/m).

Objectives: In this study, we used the Netherlands Epidemiology of Obesity (NEO) study data to identify observational and causal associations between BMI and metabolite response to a liquid meal.

Methods: A liquid meal challenge was performed, and Nightingale Health metabolite profiles were collected in 5744 NEO participants.

A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis.

Background: 'Benign ethnic neutropenia' (BEN) is a heritable condition characterized by lower neutrophil counts, predominantly observed in individuals of African ancestry, and the genetic basis of BEN remains a subject of extensive research. In this study, we aimed to dissect the genetic architecture underlying neutrophil count variation through a linear-mixed model genome-wide association study (GWAS) in a population of African ancestry (N = 5976). Malaria caused by P.

Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes.

Background: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown.

Using trials of caloric restriction and bariatric surgery to explore the effects of body mass index on the circulating proteome.

Thousands of proteins circulate in the bloodstream; identifying those which associate with weight and intervention-induced weight loss may help explain mechanisms of diseases associated with adiposity. We aimed to identify consistent protein signatures of weight loss across independent studies capturing changes in body mass index (BMI). We analysed proteomic data from studies implementing caloric restriction (Diabetes Remission Clinical trial) and bariatric surgery (By-Band-Sleeve), using SomaLogic and Olink Explore1536 technologies, respectively.

Application of Mendelian randomization to explore the causal role of the human gut microbiome in colorectal cancer.

The role of the human gut microbiome in colorectal cancer (CRC) is unclear as most studies on the topic are unable to discern correlation from causation. We apply two-sample Mendelian randomization (MR) to estimate the causal relationship between the gut microbiome and CRC. We used summary-level data from independent genome-wide association studies to estimate the causal effect of 14 microbial traits (n = 3890 individuals) on overall CRC (55,168 cases, 65,160 controls) and site-specific CRC risk, conducting several sensitivity analyses to understand the nature of results.

Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait.

Collection of genetic data at scale for a nationally representative population: the UK Millennium Cohort Study.

A DNA bank has been created from the Millennium Cohort Study (MCS) saliva samples. A total of 23,336 samples are available, from 9,259 cohort members (4,630 males and 4,629 females), 8,898 mothers and 5,179 fathers. There are 4,533 mother, child, father 'triads'.

A multivariant recall-by-genotype study of the metabolomic signature of BMI.

Objective: This study estimated the effect of BMI on circulating metabolites in young adults using a recall-by-genotype study design.

Methods: A recall-by-genotype study was implemented in the Avon Longitudinal Study of Parents and Children. Samples from 756 participants were selected for untargeted metabolomics analysis based on low versus high genetic liability for higher BMI defined by a genetic risk score (GRS).

metaboprep: an R package for preanalysis data description and processing.

Motivation: Metabolomics is an increasingly common part of health research and there is need for preanalytical data processing. Researchers typically need to characterize the data and to exclude errors within the context of the intended analysis. Whilst some preprocessing steps are common, there is currently a lack of standardization and reporting transparency for these procedures.

A framework for research into continental ancestry groups of the UK Biobank.

Background: The UK Biobank is a large prospective cohort, based in the UK, that has deep phenotypic and genomic data on roughly a half a million individuals. Included in this resource are data on approximately 78,000 individuals with "non-white British ancestry." While most epidemiology studies have focused predominantly on populations of European ancestry, there is an opportunity to contribute to the study of health and disease for a broader segment of the population by making use of the UK Biobank's "non-white British ancestry" samples.

Correction: Telford et al. Expanding the Geographic Characterisation of Epstein-Barr Virus Variation through Gene-Based Approaches. 2020, , 1686.

The authors wish to make the following correction to this paper [...

Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism.

Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We examined the genetics of variation in concentrations of postprandial metabolites ( = 150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity (NEO) study ( = 5,705).

Effects of adiposity on the human plasma proteome: observational and Mendelian randomisation estimates.

Background: Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins.

Methods: We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study.

Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort.

Mutations in the melanocortin 4 receptor gene (MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss-of-function (LoF) mutations in MC4R was ~1 in 337 (0.

Variation of microRNA expression in the human placenta driven by population identity and sex of the newborn.

Background: Analysis of lymphocyte cell lines revealed substantial differences in the expression of mRNA and microRNA (miRNA) among human populations. The extent of such population-associated differences in actual human tissues remains largely unexplored. The placenta is one of the few solid human tissues that can be collected in substantial numbers in a controlled manner, enabling quantitative analysis of transient biomolecules such as RNA transcripts.

Dietary intake of vitamin A, lung function and incident asthma in childhood.

Background: Longitudinal epidemiological data are scarce on the relationship between dietary intake of vitamin A and respiratory outcomes in childhood. We investigated whether a higher intake of preformed vitamin A or pro-vitamin β-carotene in mid-childhood is associated with higher lung function and with asthma risk in adolescence.

Methods: In the Avon Longitudinal Study of Parents and Children, dietary intakes of preformed vitamin A and β-carotene equivalents were estimated by food frequency questionnaire at 7 years of age.