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Here the authors perform a trans expression quantitative trait locus meta-analysis study of over 3,700 people and link a USP18 variant to expression of 50 inflammation genes and lupus risk, highlighting how genetic regulation of immune responses drives autoimmune disease and informs new therapies.

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.

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.

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.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

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.

The contribution of distinct subsets of macrophages to atherosclerosis is poorly understood. Here the authors describe a protective subset of vascular macrophages expressing the C-type lectin receptor CLEC4A2, which licenses monocytes to join the resident vascular macrophage pool and ensures vascular homeostasis.

Genome-wide association analysis in over one million individuals of European ancestry identifies 2,103 independent genetic signals (including 113 new loci) associated with blood pressure traits.

A multi-ancestry genome-wide gene–smoking interaction study identifies 13 new loci associated with serum lipids.

GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.

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.

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.

Mendelian randomization (MR) identifies causal relationships from observational data but has increased error rates when the genetic variants used as instruments come from a single region, a typical scenario when assessing molecular traits like protein or metabolite levels as risk factors. Here the authors introduce a single-region pleiotropy-robust MR method, validating the method on three ground truth sources, showing its capability to identify disease-causing molecular traits.

The authors perform meta-analysis of GWAS studies for asthma from multiancestral cohorts. They identify five new loci and find that the asthma-associated loci are enriched near enhancer marks in immune cells.

Multi-ancestry genome-wide association analyses and systematic variant-to-gene mapping strategies implicate new genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

A meta-analysis of genome-wide association studies for 233 circulating metabolites from 33 cohorts reveals more than 400 loci and suggests probable causal genes, providing insights into metabolic pathways and disease aetiology.

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.

Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

Aarno Palotie and colleagues present results of a large genome-wide association study of migraine. They identified significant associations at 38 distinct loci and found enrichment for genes expressed in vascular and smooth muscle tissues.

Multi-ancestry genome-wide association meta-analysis identifies new risk loci for CAC. Functional evidence implicates candidate causal genes as regulators of smooth muscle cell-mediated calcification.

Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke.

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.

Association analyses in over 1 million individuals identify 535 new loci influencing blood pressure traits. The results provide new insights into blood pressure regulation and highlight shared genetic architecture between blood pressure and lifestyle exposures.

An expanded GWAS of birth weight and subsequent analysis using structural equation modeling and Mendelian randomization decomposes maternal and fetal genetic contributions and causal links between birth weight, blood pressure and glycemic traits.

Sleep duration is associated with an adverse lipid profile. Here, the authors perform genome-wide gene-by-sleep interaction analysis and find 49 previously unreported lipid loci when considering short or long total sleep time.

A genetic study identifies hundreds of loci associated with risk tolerance and risky behaviors, finds evidence of substantial shared genetic influences across these phenotypes, and implicates genes involved in neurotransmission.

Here, the authors present a TWAS framework OTTERS that adapts multiple polygenic risk score methods to estimate eQTL weights from summary-level eQTL data. Both simulation and real studies show OTTERS is powerful across a wide range of genetic architectures.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

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.

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.

Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants.

Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.