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Genome-wide association analyses of 249 circulating small molecules and lipoprotein characteristics across the allele frequency spectrum in UK Biobank advance understanding of genes and pathways regulating human metabolism.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Chronic kidney disease (CKD) is a common condition and its prevalence is increasing. Prognosis is poor, with many patients experiencing disease progression. Recognizing the factors associated with CKD progression would enable high-risk patients to be identified and given more intensive treatment if necessary. The identification of new predictive markers might improve our understanding of the pathogenesis and progression of CKD. Here, Florian Kronenberg discusses various emerging factors and markers for which epidemiological evidence from prospective studies has shown an association with CKD progression.

Many genetic loci have been identified to be associated with kidney disease, but the molecular mechanisms are not well understood. Here, the authors perform epigenome-wide association studies on kidney function measures to identify epigenetic marks and pathways involved in kidney function.

Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies.

Metabolites are indicators of health and disease; genetic studies can reveal variants influencing their levels. Here, the authors investigate the contribution of rare, exonic variants on the levels of urine metabolites and generate predictions on metabolic consequences underlying metabolic disease.

Genome-wide studies of 1,916 plasma and urine metabolites from 5,023 participants of the German Chronic Kidney Disease study provide insights into systemic and kidney-specific enzymatic and transport processes.

Genome-wide association analysis of 1,172 urinary metabolites identifies 240 metabolite–locus associations that when combined with UK Biobank data suggest novel metabolic mediators of disease and markers of disease risk.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Trans-ethnic analyses of exome array data identify new risk loci for type 2 diabetes. Fine-mapping analyses using genome-wide association data show that the index coding variants represent the likely causal variants at only a subset of these loci.

Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits. Here the authors identify and replicate 100 urate-associated CpGs, which provide insights into urate GWAS loci and shared CpGs of urate and cardiometabolic traits.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Checkpoint blocking therapies are used to treat metastatic melanoma, but can have adverse immune-mediated effects, including liver pathology. Here the authors identify an expanded pool of CD4⁺ effector memory T cells resulting from prior CMV exposure as a risk factor for this adverse effect in these patients.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

Christopher Newton-Cheh and colleagues report genome-wide association analyses for QT interval, an electrocardiographic measure reflecting myocardial repolarization, in 100,000 individuals. They identify 35 loci associated with QT interval and highlight a role for calcium regulation in myocardial repolarization.

Caroline Fox and colleagues report results of a large genome-wide association meta-analysis and replication study for indices of renal function. Their work identifies 13 new loci associated with renal function and 7 loci associated with creatinine production and secretion.

Genome-wide association analyses identify 30 risk loci for IgA nephropathy. Functional annotations of putative causal genes converge on inflammatory signaling pathways and cytokine ligand–receptor pairs, prioritizing potential new drug targets.

Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.

Trans-ancestry meta-analysis of estimated glomerular filtration rate (eGFR) from 1,046,070 individuals identifies 264 associated loci, providing a resource of molecular targets for translational research of chronic kidney disease.

Lipid concentration in the serum is one of the most important risk factors for coronary artery disease and can be targeted for therapeutic intervention. A genome-wide association study in >100,000 individuals of European ancestry now finds 95 significantly associated loci that also affect lipid traits in non-European populations. Among associated loci are those involved in cholesterol metabolism, known targets of cholesterol-lowering drugs and those that contribute to normal variation in lipid traits and to extreme lipid phenotypes.

A trans-ancestry genome-wide association study of serum urate levels identifies 183 loci influencing this trait. Enrichment analyses, fine-mapping and colocalization with gene expression in 47 tissues implicate the kidney and liver as key target organs and prioritize potential causal genes.

The re-wiring of the metabolic machinery is a common feature in cancer. Here, the authors show, using paired normal and prostate cancer samples that the cancer samples exhibit a shift to succinate respiration, which is associated with elevated levels of mitochondrial DNA mutations.

Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.

Karsten Suhre and colleagues report a genome-wide association study of metabolic traits in human urine, using NMR spectrometry to measure 59 metabolites in urine from participants. They identify five loci influencing urine metabolite levels and point to a missense variant in AGXT2 as the likely cause of hyper-β-aminoisobutyric aciduria, a common inborn error of metabolism.

Melinda Mills, Nicola Barban, Harold Snieder, Marcel den Hoed and colleagues perform a meta-analysis of data from over 300,000 individuals for age at first birth and number of children ever born. They identify 12 significant loci that associate with these traits, providing insights into the genetic basis of human reproductive behavior.

Martin Tobin and colleagues report a meta-analysis of 23 genome-wide association studies for pulmonary function. They identify 16 loci newly associated with variation in two cross-sectional measures of lung function, used to define airway obstruction and to grade the severity of obstruction.

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

Leena Peltonen and colleagues report a genome-wide association study of cholesterol and triglyceride levels in 16 population-based cohorts across Europe. Six new loci were identified, and overall a genetic risk score improves the screening of high risk groups for dyslipidemia.

Karsten Suhre and colleagues report a genome-wide association study to 163 metabolic traits in human serum.

Christian Fuchsberger, Gonçalo Abecasis and colleagues describe a new web-based imputation service that enables rapid imputation of large numbers of samples and allows convenient access to large reference panels of sequenced individuals. Their state space reduction provides a computationally efficient solution for genotype imputation with no loss in imputation accuracy.