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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.

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.

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.

Anna Köttgen and colleagues report genome-wide association studies for serum urate in over 140,000 individuals from the Global Urate Genetics Consortium (GUGC). They identify 18 loci newly associated with serum urate concentrations and confirm 10 known loci, characterize their associations with gout and include a network analysis suggesting a role for inhibins-activins pathways in regulating urate homeostasis.

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.

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.

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.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Gene-based rare variant aggregation study with the levels of 1,294 plasma and 1,396 urine metabolites from paired specimens of 4,737 participants reveals graded effects of rare, putatively damaging variants on gene function and human traits.

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.

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.

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.

Persistently low levels of estimated glomerular filtration rate (eGFR) are a biomarker of chronic kidney disease. Here, the authors reinterpret the genetic architecture of kidney function across ancestries, to identify not only genes, but the tissue and anatomical contexts of renal homeostasis.

Genome-wide association studies (GWAS) have shed light on the genetic basis of chronic kidney disease (CKD). Here, Matthias Wuttke and Anna Köttgen discuss the findings of GWAS of CKD-defining traits and of GWAS of specific CKD aetiologies and their follow-up experimental and epidemiological studies, as well as their implications for future study design.

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.

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.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases such as chronic kidney disease (CKD). Here, the authors perform a sex-stratified, cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits, with results including identification of four novel loci associated with the CKD-defining trait eGFR.

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.

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.

Elevated serum urate levels are a risk factor for gout. Here, Tin et al. perform whole-exome sequencing in 19,517 individuals and detect low-frequency genetic variants in urate transporter genes, SLC22A12 and SLC2A9, associated with serum urate levels and confirm their damaging nature in vitro and in silico.

An exome wide association study of UK Biobank data revealed 158 variants and 105 genes significantly associated with kidney function traits and disease. The findings are supported by functional evidence for a previously unreported mutation in CLDN10.

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.

Genetic, epigenetic and transcriptomic studies in hyperuricaemia and gout have, in the past 6 years, provided important insights into the underlying molecular mechanisms, revealing new inflammatory pathways and epigenetic factors and expanding research beyond European populations.

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.

The lactate metabolite N-lactoyl-phenylalanine (Lac-Phe) plays a role in suppressing food intake and body weight. Here, the authors identify kidney transporters responsible for the renal excretion of Lac-Phe. This discovery highlights a pathway for Lac-Phe regulation in mice and humans.

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.

Membranous nephropathy (MN) is a rare autoimmune disease of podocyte-directed antibodies, such as anti-phospholipase A2 receptor. Here, the authors report a genome-wide association study for MN and identify two previously unreported loci encompassing the NFKB1 and IRF4 genes and additional ancestry-specific effects.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Nona Sotoodehnia and colleagues report a meta-analysis of 14 genome-wide association studies for QRS interval, an electrocardiogram measurement of cardiac ventricular conduction. They identify 22 loci associated with QRS duration.

Emelia Benjamin and colleagues report a meta-analysis of genome-wide association study data for atrial fibrillation, a condition associated with stroke and heart failure, in five European community-based cohorts of the CHARGE consortium. They report an association in ZFHX3 to atrial fibrillation, with replication in an independent cohort from the German AF Network.

Thyroid dysfunction is involved in many diseases. Here, the authors provide insights into the genetics and biological pathways influencing important thyroid function parameters, showing potential causal effects on many clinical outcomes.

Chronic inflammation, marked by C-reactive protein, has been associated with changes in methylation, but the causal relationship is unclear. Here, the authors perform a Epigenome-wide association meta-analysis for C-reactive protein levels and find that these methylation changes are likely the consequence of inflammation and could contribute to disease.

Despite Africa’s vast genetic diversity, its populations are underrepresented in global genomic datasets. Here we describe the vision of the KidneyGenAfrica, a pan-African initiative launched to address this inequity, and call for more inclusive genomics research that recognizes Africa’s key role in genetic variation and potential to generate insights in chronic kidney disease.

The slit-diaphragm is a cellular junction that is crucial for blood filtration in the kidney. Kocylowski et al. show that the junction-spanning components are embedded in a protein network for dynamic control of filtration; network disturbance leads to severe filtration defects with proteinuria.

Chronic kidney disease (CKD) is often well advanced before it is detected. Although polygenic scores may enable the early stratification of patients at risk of CKD, the transferability of polygenic scores for the prediction of CKD to populations of non-European ancestry was limited. A new cross-ancestry polygenic score for CKD overcomes these issues, demonstrating good performance across ancestries.

Analyses of cis-genetic regulation of the plasma proteome in European and African American populations lead to the identification of shared and unique cis-protein quantitative trait loci and models for proteome-wide association studies of complex traits.

Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.

Genome-wide association studies of kidney function show enrichment of associated genetic variants in regulatory regions. Here, the authors perform epigenome-wide association studies of kidney function and disease, identifying 19 CpG sites significantly associated with these.

Santhi Ganesh and colleagues report meta-analyses of genome-wide association studies of six erythrocyte traits within the CHARGE consortium, with replication in cohorts of the HaemGen consortium. They report 23 loci associated with a range of clinically relevant red blood cell traits.

Daniel Levy and colleagues report a meta-analysis of genome-wide association studies for blood pressure traits as part of the CHARGE consortium, reporting eight loci with replicated association to systolic and/or diastolic blood pressure, with one of these loci also associated to hypertension.

Caroline Fox and colleagues report results of a genome-wide association study to identify common variants associated with indices of renal function. They show that variants at UMOD, a gene previously implicated in rare monogenic forms of kidney disease, are associated with risk of chronic kidney disease in the general population.

Arne Pfeufer, Aravinda Chakravarti and colleagues from the QTSCD consortium report genetic associations influencing the QT interval duration, a measure of cardiac repolarization which is a risk factor for sudden cardiac death, in five genome-wide association studies.