Single cell multiome profiling of pancreatic islets reveals physiological changes in cell type-specific regulation associated with diabetes risk.

Physiological variability in pancreatic cell type gene regulation and the impact on diabetes risk is poorly understood. In this study we mapped gene regulation in pancreatic cell types using single cell multiomic (joint RNA-seq and ATAC-seq) profiling in 28 non-diabetic donors in combination with single cell data from 35 non-diabetic donors in the Human Pancreas Analysis Program. We identified widespread associations with age, sex, BMI, and HbA1c, where gene regulatory responses were highly cell type- and phenotype-specific.

Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease.

Background: A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene () are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia.

Methods: To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls.

RNA-seq analysis of the human surfactant air-liquid interface culture reveals alveolar type II cell-like transcriptome.

Understanding pulmonary diseases requires robust culture models that are reproducible, sustainable in long-term culture, physiologically relevant, and suitable for assessment of therapeutic interventions. Primary human lung cells are physiologically relevant but cannot be cultured long term and, although engineered organoids are an attractive choice, they do not phenotypically recapitulate the lung parenchyma; overall, these models do not allow for the generation of reliable disease models. Recently, we described a new cell culture platform based on H441 cells that are grown at the air-liquid interface to produce the SALI culture model, for studying and correcting the rare interstitial lung disease surfactant protein B (SPB) deficiency.

POINT technology illuminates the processing of polymerase-associated intact nascent transcripts.

Mammalian chromatin is the site of both RNA polymerase II (Pol II) transcription and coupled RNA processing. However, molecular details of such co-transcriptional mechanisms remain obscure, partly because of technical limitations in purifying authentic nascent transcripts. We present a new approach to characterize nascent RNA, called polymerase intact nascent transcript (POINT) technology.

A non-linear regression method for estimation of gene-environment heritability.

Motivation: Gene-environment (GxE) interactions are one of the least studied aspects of the genetic architecture of human traits and diseases. The environment of an individual is inherently high dimensional, evolves through time and can be expensive and time consuming to measure. The UK Biobank study, with all 500 000 participants having undergone an extensive baseline questionnaire, represents a unique opportunity to assess GxE heritability for many traits and diseases in a well powered setting.

Inferring Gene-by-Environment Interactions with a Bayesian Whole-Genome Regression Model.

The contribution of gene-by-environment (GxE) interactions for many human traits and diseases is poorly characterized. We propose a Bayesian whole-genome regression model for joint modeling of main genetic effects and GxE interactions in large-scale datasets, such as the UK Biobank, where many environmental variables have been measured. The method is called LEMMA (Linear Environment Mixed Model Analysis) and estimates a linear combination of environmental variables, called an environmental score (ES), that interacts with genetic markers throughout the genome.

Heterozygous Gene Deficiency and Risk of Coronary Artery Disease.

Background: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

A-to-I RNA Editing Uncovers Hidden Signals of Adaptive Genome Evolution in Animals.

In animals, the most common type of RNA editing is the deamination of adenosines (A) into inosines (I). Because inosines basepair with cytosines (C), they are interpreted as guanosines (G) by the cellular machinery and genomically encoded G alleles at edited sites mimic the function of edited RNAs. The contribution of this hardwiring effect on genome evolution remains obscure.

Genetic Landscapes Reveal How Human Genetic Diversity Aligns with Geography.

Geographic patterns in human genetic diversity carry footprints of population history and provide insights for genetic medicine and its application across human populations. Summarizing and visually representing these patterns of diversity has been a persistent goal for human geneticists, and has revealed that genetic differentiation is frequently correlated with geographic distance. However, most analytical methods to represent population structure do not incorporate geography directly, and it must be considered post hoc alongside a visual summary of the genetic structure.

Stochastic search and joint fine-mapping increases accuracy and identifies previously unreported associations in immune-mediated diseases.

Thousands of genetic variants are associated with human disease risk, but linkage disequilibrium (LD) hinders fine-mapping the causal variants. Both lack of power, and joint tagging of two or more distinct causal variants by a single non-causal SNP, lead to inaccuracies in fine-mapping, with stochastic search more robust than stepwise. We develop a computationally efficient multinomial fine-mapping (MFM) approach that borrows information between diseases in a Bayesian framework.

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178).

Rare Protein-Truncating Variants in APOB, Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease.

Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD.

The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes.

Background: Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development of autoimmunity to pancreatic β cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance of immunosuppressive functions. Using a response-adaptive design, we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of Teffs.

Publisher Correction: Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans.

In the supplementary information PDF originally posted, there were discrepancies from the integrated supplementary information that appeared in the HTML; the former has been corrected as follows. In the legend to Supplementary Fig. 2c, "major organs of the mouse" has been changed to "major organs of the adult mouse.

Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans.

The formation of the vertebrate brain requires the generation, migration, differentiation and survival of neurons. Genetic mutations that perturb these critical cellular events can result in malformations of the telencephalon, providing a molecular window into brain development. Here we report the identification of an N-ethyl-N-nitrosourea-induced mouse mutant characterized by a fractured hippocampal pyramidal cell layer, attributable to defects in neuronal migration.

Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.

Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach.

A Novel Mutation Interacts with the Nonobese Diabetic Genetic Background To Cause Autoimmune Cholangitis.

We previously reported that NOD.c3c4 mice develop spontaneous autoimmune biliary disease (ABD) with anti-mitochondrial Abs, histopathological lesions, and autoimmune T lymphocytes similar to human primary biliary cholangitis. In this article, we demonstrate that ABD in NOD.

Genetic and epigenetic studies of adiposity and cardiometabolic disease.

Over 300 million adults are obese, but little is known about the impact of obesity on cardiovascular health. We discuss recent genetic and epigenetic studies of adiposity that indicate a causal role for general and central adiposity in cardiometabolic disease, and highlight potential mechanisms including insulin resistance and gene expression.

Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial.

Background: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen.

Methods: Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel.

Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.

The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions (P < 5 × 10) that are associated with mLOY.

Genome-wide genetic analyses highlight mitogen-activated protein kinase (MAPK) signaling in the pathogenesis of endometriosis.

Study Question: Do genome-wide association study (GWAS) data for endometriosis provide insight into novel biological pathways associated with its pathogenesis?

Summary Answer: GWAS analysis uncovered multiple pathways that are statistically enriched for genetic association signals, analysis of Stage A disease highlighted a novel variant in MAP3K4, while top pathways significantly associated with all endometriosis and Stage A disease included several mitogen-activated protein kinase (MAPK)-related pathways.

What Is Known Already: Endometriosis is a complex disease with an estimated heritability of 50%. To date, GWAS revealed 10 genomic regions associated with endometriosis, explaining <4% of heritability, while half of the heritability is estimated to be due to common risk variants.

Haemodynamics Regulate Fibronectin Assembly via PECAM.

Fibronectin (FN) assembly and fibrillogenesis are critically important in both development and the adult organism, but their importance in vascular functions is not fully understood. Here we identify a novel pathway by which haemodynamic forces regulate FN assembly and fibrillogenesis during vascular remodelling. Induction of disturbed shear stress in vivo and in vitro resulted in complex FN fibril assembly that was dependent on the mechanosensor PECAM.