Mutational signature analyses in multi-child families reveal sources of age-related increases in human germline mutations.

Whole-genome sequencing studies of parent-offspring trios have provided valuable insights into the potential impact of de novo mutations (DNMs) on human health and disease. However, the molecular mechanisms that drive DNMs are unclear. Studies with multi-child families can provide important insight into the causes of inter-family variability in DNM rates but they are highly limited.

Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans.

Background: Apolipoprotein L1 gene () variants are risk factors for chronic kidney disease (CKD) among Black Americans. Data are sparse on the genetic epidemiology of CKD and the clinical association of variants with CKD in West Africans, a major group in the Black population.

Methods: We conducted a case-control study involving participants from Ghana and Nigeria who had CKD stages 2 through 5, biopsy-proven glomerular disease, or no kidney disease.

Association of with Coronary Artery Calcium Differs by Sex and Cigarette Smoking.

Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study ( = 6144 participants of European ancestry and = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group).

Integrated multi-omic analyses uncover the effects of aging on cell-type regulation in glucose-responsive tissues.

Aging significantly influences cellular activity and metabolism in glucose-responsive tissues, yet a comprehensive evaluation of the impacts of aging and associated cell-type responses has been lacking. This study integrates transcriptomic, methylomic, single-cell RNA sequencing, and metabolomic data to investigate aging-related regulations in adipose and muscle tissues. Through coexpression network analysis of the adipose tissue, we identified aging-associated network modules specific to certain cell types, including adipocytes and immune cells.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways.

Multiomics Analyses Identify AKR1A1 as a Biomarker for Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Because many genes associate with DKD, multiomics approaches were used to narrow the list of functional genes, gene products, and related pathways providing insights into the pathophysiological mechanisms of DKD. The Kidney Precision Medicine Project human kidney single-cell RNA-sequencing (scRNA-seq) data set and Mendeley Data on human kidney cortex biopsy proteomics were used.

APOL1-mediated and Mendelian forms of "heretofore" idiopathic collapsing glomerulopathy: lessons from Brazil.

APOL1-mediated kidney diseases have forever changed nephrology and kidney transplantation. Neves et al. extend this field with analyses in admixed Brazilians with the most severe type of APOL1-mediated kidney disease, idiopathic collapsing glomerulopathy.

Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.

Background: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

Methods: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program.

Methods for estimating insulin resistance from untargeted metabolomics data.

Context: Insulin resistance is associated with multiple complex diseases; however, precise measures of insulin resistance are invasive, expensive, and time-consuming.

Objective: Develop estimation models for measures of insulin resistance, including insulin sensitivity index (SI) and homeostatic model assessment of insulin resistance (HOMA-IR) from metabolomics data.

Design: Insulin Resistance Atherosclerosis Family Study (IRASFS).

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point.