Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Cell Specific eQTL Analysis without Sorting Cells

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn’s disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income&nbsp;countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was &lt;1.1 kg m–2 in the vast majority of&nbsp;countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified

Fifteen Genetic Loci Associated with the Electrocardiographic P Wave

The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies. Methods and Results - We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction. Conclusions - We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias

The DZHK research platform: maximisation of scientific value by enabling access to health data and biological samples collected in cardiovascular clinical studies

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for