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Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Stroke is a multifactorial disease influenced by genetic and environmental factors. Here, the authors apply exome-wide association analysis to find rare coding variants associated with stroke in a Pakistani cohort, finding a significant association of a variant in NOTCH3 that is highly enriched in South Asians.

Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

Genomic studies often lack representation from diverse populations, limiting equitable insights. Here, the authors show that the BIG Initiative captures extensive genetic diversity and reveals ancestry-linked health disparities in a community-based Mid-South cohort.

Genome-wide analyses identify variants associated with sinus node dysfunction, distal conduction disease and pacemaker implantation, implicating ion channel function, cardiac developmental programs and sarcomeric structure in bradyarrhythmia susceptibility.

Analysis of exome sequencing data identifies a burden of rare coding variants in 19 genes associated with bone mineral density. Integrated analyses show convergence of common- and rare-variant signals and highlight likely effector genes influencing osteoporosis risk.

Patches in primary visual cortex (V1) rich in cytochrome oxidase were thought to contain unoriented, color-opponent neurons. Here the authors measure orientation tuning in V1 neurons using acutely implanted 100-electrode arrays. Patch cells were nearly as well tuned as those in interpatches, suggesting that processing of form and color is not strictly segregated in primate V1. Patch cells had higher mean discharge rates, consistent with their enhanced metabolism.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

A dataset of coding variation, derived from exome sequencing of nearly one million individuals from a range of ancestries, provides insight into rare variants and could accelerate the discovery of disease-associated genes and advance precision medicine efforts.

Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.

Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.

Fat distribution is associated with cardiometabolic disease, although it has been less well studied than overall obesity. In a multiancestry exome-sequencing study, the authors identified predicted loss-of-function mutations in INHBE associated with favorable fat distribution and protection from type 2 diabetes.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

Genome-wide association meta-analyses among 1.4 million individuals identify 318 new risk loci for type 2 diabetes and provide insight into the contribution of these risk variants to diabetes-related vascular outcomes.

Genome-wide analyses identify variants in B3GALT5 and ST6GAL1 associated with influenza susceptibility. Knockdown of ST6GAL1 in cell culture reduces influenza infectivity, likely by interfering with the glycoprotein modifications required for viral entry.

An exome-wide association study of six smoking phenotypes in up to 749,459 individuals identifies associations of rare coding variants in CHRNB2 that may reduce the likelihood of smoking.

Genome-wide meta-analysis of SARS-CoV-2 susceptibility and severity phenotypes in up to 756,646 samples identifies a rare protective variant proximal to ACE2. A 6-SNP genetic risk score provides additional predictive power when added to known risk factors.

Analysis of whole-exome sequencing data from over 200,000 individuals in the UK Biobank provides new insights into the contribution of rare variants to cardiometabolic diseases and traits.

Trans-ancestry genome-wide analyses identify multiple loci associated with ascending aortic diameter. A polygenic score constructed from these loci predicted prevalent risk of thoracic aortic aneurysm in independent populations.

Bone mineral density (BMD) is associated with fracture risk and many genetic loci with small effect sizes have been discovered by genome-wide association studies (GWAS). Here, the authors discover a large-effect rare loss-of-function genetic variant for BMD in the MEPE gene in the Norwegian HUNT study which replicates in the UK Biobank.

Genome-wide association and genetic risk score analyses highlight differences in genetic architecture across five subtypes of diabetes.

The most comprehensive survey of clinical success rates across the drug industry to date shows productivity may be even lower than previous estimates.

Rare variant association data from human genetics combined with in vitro and in vivo functional validation highlight ANGPTL7 as a promising therapeutic target for intraocular pressure reduction, and protection from glaucoma.

A GWAS and exome-wide association study meta-analysis identifies 53 loci affecting hearing loss risk from over half a million individuals across five cohorts. Rare variants in Mendelian hearing loss genes contribute to hearing loss risk in adults.

The UK Biobank Exome Sequencing Consortium aims to sequence all the exomes of approximately 500,000 UK Biobank participants. This Perspective describes the results from approximately 200,000 exomes and discusses the lessons learned from this UK Biobank–biopharmaceutical company collaboration.