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Analyses of leukocyte telomere length in All of Us identify associations with various lifestyle, socioeconomic and disease traits. Genome-wide analyses combining All of Us with UK Biobank data discover new loci contributing to telomere length variation.

Types of clonal hematopoiesis (CH) differ in frequency and fitness. These findings uncover shared genetic architecture, suggest evolutionary trade-offs between CH types, and detail elevated leukemia risk in individuals with overlapping types of CH.

Here, the authors use passenger mutations to quantify expansion rate in ~6,000 people with mosaic chromosomal alterations in the NHLBI TOPMed cohort, finding associations between growth rate and blood counts along with germline genetic modulators of growth rate.

In CHIP, somatic mutations in a hematopoietic stem cell lead to a clonal subpopulation of blood cells. Here, the authors perform a CHIP meta-EWAS to establish its epigenetic features and age-related outcomes.

A method that allows for the detection of mosaic chromosomal alterations from blood whole-genome sequencing data highlights ancestry-specific differences in the distribution of common and rare germline susceptibility variants.

This study explores the relationship between telomere length and clonal hematopoiesis. Splicing factor and PPM1D gene mutations are more frequent in people with genetically predicted shorter telomere lengths, suggesting that these mutations protect against the consequences of telomere attrition.

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases but the underlying factors driving its development are largely unknown. Here, longitudinal assessment of 4,187 participants over 21 years provides insights into cell-intrinsic and -extrinsic factors contributing to the development and progression of CHIP clones in older adults.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Somatic mutations in blood cells (CHIP) are linked to diseases like heart disease, but the mechanisms are unclear. Here, the authors show that different CHIP driver genes alter unique sets of plasma proteins, some of which are validated in mouse models.

Here the authors develop a novel statistical method for quantifying mutation burden from whole genome sequencing data and use it to discover the genetic, genomic, and phenotypic correlates of clonal hematopoiesis without known driver genetic lesions.

Clonal hematopoiesis, often caused by mutations in DNMT3A and TET2, is associated with blood cancer and coronary artery disease. Here, the authors conduct an epigenome-wide association study, finding that clonal hematopoiesis caused by DNMT3A vs. TET2 mutations has directionally opposing changes in DNA methylation profiles, with both promoting stem cell self-renewal.

The relationship between pathogenic germline variation, clonal hematopoiesis (CH) and risk of hematologic malignancy is explored in 731,835 individuals across 6 cohorts. Carriers of variants in certain genes show distinct patterns of CH and increased risk of CH progression to malignancy.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

Here, the authors evaluate T-cell fraction genetics in diverse populations, explaining up to 42% heritability and identifying 14 putatively causal variants. They link T-cell fraction to blood traits and sex-specific conditions like pregnancy.

In an analysis of five large randomized clinical trials testing established therapies for cardiovascular disease, individuals with clonal hematopoiesis had an increased risk for first but not recurrent myocardial infarction as compared to individuals without clonal hematopoiesis, and did not show increased benefit from any of the therapies tested.

Clonal hematopoiesis, which increases with age and is implicated in a variety of age-related diseases, is shown here to be associated with a greater risk of acute kidney injury and worse outcome following injury, as demonstrated using multiple patient cohorts, Mendelian randomization analysis and mechanistic studies in mouse disease models.

Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.

The emergence of large-scale genomics projects has led to genetic studies across cohorts. Here, the authors conduct genome-wide association studies meta-analyzing in trusted research environments or pooling together and find similar, but not identical results.

Zekavat, Matesanz, Viana-Huete et al. show an increased risk of peripheral artery disease and atherosclerosis in different vascular beds in patients with clonal hematopoiesis of indeterminate potential (CHIP) caused by mutations in DNA damage repair genes, such as TP53. Validations in a mouse model support the causal contribution of TP53-mutant CHIP to atherosclerosis.

Exploring the clonal expansion of somatically mutated hematopoietic stem cells with aging, Mack, Raddatz et al. quantify rates of clonal expansion in 4,370 individuals in the Trans-Omics for Precision Medicine cohort, observing epigenetic and proteomic patterns associated with clonal hematopoiesis of indeterminate potential.

A large-scale meta-analysis across eight biobank datasets identifies common genetic variants associated with mosaic loss of the X chromosome in female participants.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

A combined-ancestry GWAS of diabetic retinopathy, comprising 68,169 cases and 129,188 controls, revealed nine previously unreported loci associated with the condition, including an evolutionarily adaptive genetic variant alongside a potential functional mechanism that influences racial disparities in diabetes complications among individuals of non-Hispanic African ancestry.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

The burden of mosaic chromosomal alterations in blood-derived DNA, a type of clonal hematopoiesis, is associated with an increased risk for diverse types of infections, including sepsis and pneumonia.

A genome-wide association study identifies 17 genetic loci that are associated with the risk of myeloproliferative neoplasms (MPNs), and shows that the modulation of haematopoietic stem cell function drives MPN risk.

Clonal hematopoiesis of indeterminate potential (CHIP) was found to be associated with a protective effect from Alzheimer’s disease (AD) in large population-based cohorts.

Silver, Bick and Savona discuss our latest understanding of clonal haematopoiesis (CH), which is an expansion of blood cell populations with shared somatic mutations. They focus on human germline risk variants and on how these are linked to different forms of CH and their associated disease pathologies.

To overcome limitations of previous genome-wide association studies of coronary artery disease, this study incorporates a cohort of individuals containing large fractions of Black and Hispanic individuals to provide a wider view of the genetic landscape of this disease.

Genomic analyses in the UK Biobank show that clonal hematopoiesis of indeterminate potential in the lymphoid lineage is associated with a higher risk of developing lymphoid malignancies

Genome-wide association analyses identify variants associated with thoracic aortic diameter. A polygenic score for ascending aortic diameter was associated with a diagnosis of thoracic aortic aneurysm in independent samples.

A study describes the release of clinical-grade whole-genome sequence data for 245,388 diverse participants by the All of Us Research Program and characterizes the properties of the dataset.

Structural changes to the left ventricle are characteristic of dilated cardiomyopathy (DCM), a disease for which many rare genetic variants are known. Here, Pirruccello et al. report GWAS of seven cardiac MRI measurements in the left ventricle and describe shared loci and polygenic association with DCM.

Genetic variation predisposes to disease via monogenic and polygenic risk variants. Here, the authors assess the interplay between these types of variation on disease penetrance in 80,928 individuals. In carriers of monogenic variants, they show that disease risk is a gradient influenced by polygenic background.

Liu et al. report that the IL-6R antibody reduces the atherosclerosis promoted by Tet2 clonal hematopoiesis (CH) via reversal of increased macrophage colony-stimulating factor 1 receptor expression and suggests blocking IL-6 signaling as a potential therapy for CH-driven cardiovascular disease.

By conducting a large multi-ancestry GWAS of varicose veins followed by bioinformatics analyses, Levin et al. identified new and recurrent causal variants, traits with shared genetic mechanisms, and putative causal risk factors of the disease, revealing its polygenic architecture and genetic overlap with arterial and venous disease and identifying potential therapeutic targets.

Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.

Recovery of 1,167 nonredundant archaeal genomes from the human gut microbiomes reveals previously undescribed genera, associations with sociodemographic factors and the presence of an archaeal virome.

Clonal hematopoiesis is a risk factor for hematological cancers, cardiovascular diseases and death. Two papers now use new experimental and mathematical tools to quantify changes in the clonal composition of human blood over time, and the results have implications for the risk of cardiovascular diseases.

Pioneering cohort studies including the Framingham Heart Study have led to major insights into cardiovascular disease. However, these studies are underpowered to identify the effects of less common risk factors on human health. This has motivated the development of the UK Biobank, a biomedical database linking health and genetic information in 500,000 individuals.