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This study in the Finnish population reveals genetic reduction of the complement factor CFHR5 as enhancing retinal health and reducing the risk for age-related macular degeneration (AMD), suggesting new strategies for AMD prevention and treatment.

Study shows PTSD predisposition shares distinct genes and genomic regions with several cardiovascular conditions. Here the findings reveal neuronal, immune, and metabolic pathways, and repurposed drug targets that further the understanding of the comorbidity.

Studying the contribution of pairs of genes to complex traits has been challenging. Here, the authors combine exome and genotype data with RNAi to screen for genetic interactions between 30 genes identified in lipid GWAS to hint at pairs whose joint modulation may improve lipid-lowering therapies.

A genome-wide association study identifies 17 genetic loci that are associated with the risk of myeloproliferative neoplasms (MPNs), and shows that the modulation of haematopoietic stem cell function drives MPN risk.

Brain expression quantitative trait locus (eQTL) and network analyses encompassing 8,613 RNA-sequencing samples from 14 eQTL datasets reveal downstream effects and putative drivers for brain-related diseases.

A meta-analysis combining whole-exome sequencing data from UK Biobank participants and imputed genotypes from FinnGen participants enables identification of genetic associations with human disease in the rare and low-frequency allelic spectrum

Despite many common genetic variants being linked to depression, the impact of rare coding variants on depression remains largely unknown. Here, the authors perform a whole-exome sequencing study of depression, providing insights into the rare genetic architecture of depression.

In a large and prospective cohort, higher polygenic risk is associated with higher risk and earlier age of onset for cardiometabolic disorders and cancer, and has added value to clinical risk scores in clinical disease prediction.

Integrative analyses of whole-blood gene expression and splicing QTLs with protein, metabolite and lipid QTLs from the same individuals shed light on the shared genetic architecture of molecular traits and health outcomes.

Here, the authors leveraged genetic and proteomic information from the UK Biobank and two randomized controlled trials to characterize how polygenic disease risk for T2D and related comorbidities perturbs the plasma proteome and glean therapeutic insights.

Blood biomarkers in a middle-aged population suggest that SARS-CoV-2 infection is associated with greater brain β-amyloid plaque accumulation.

Here, the authors provide an exome study of hand grip strength, a proxy of generalized muscle strength. They identify six exome-wide significant genes, with links to disease, and additivity of rare and common genetic variant effects on muscle strength.

Analysis of rare coding variants in the UK Biobank identifies eight genes associated with adult cognitive function, including KDM5B. Rare and common variant signals overlap and contribute additively to the phenotype.

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.

A genetic atlas of the human plasma proteome, comprising 1,927 genetic associations with 1,478 proteins, identifies causes of disease and potential drug targets.

Testing the association between genetic variants and a range of phenotypes can assist drug development. Here, in a phenome-wide association study in up to 697,815 individuals, Diogo et al. identify genotype–phenotype associations predicting efficacy, alternative indications or adverse drug effects.

Here, the authors integrate genomic, proteomic, and phenotypic data from UK Biobank, identifying over 1,100 gene-environment interactions. They catalogue interactions between 101 blood proteins and 153 exposures, which may refine biomarker discovery.

Immune system dysfunction has been implicated in the development of dementias, but its causal role remains unknown. Providing converging results from different lines of human research, this study by Lindbohm et al. suggests that autoimmunity may be a modifiable component in diseases causing dementia.

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

Tom Karlsen and colleagues report a genome-wide association study for primary sclerosing cholangitis, a chronic bile duct disease. They identify susceptibility loci at MST1 and near BCL2L11.

A set of three papers in Nature reports a new proteomics resource from the UK Biobank and initial analysis of common and rare genetic variant associations with plasma protein levels.

This study demonstrates that the burden of protein-truncating variants identified through population-scale exome sequencing impacts how long we live. The authors report four distinct human lifespan genes with roles in cancer and clonal hematopoiesis.

Genetic associations with particular patterns of brain folding may provide insight into brain development and function. Here, the authors identify and replicate 388 genetic associations with brain sulcal morphology across 40,169 UK Biobank MRI scans, revealing insights into the processes guiding cortical development and genetic correlations with neuropsychiatric phenotypes.

Genome-wide association studies of individuals from an isolated population (data from the Finnish biobank study FinnGen) and consequent meta-analyses facilitate the identification of previously unknown coding variant associations for both rare and common diseases.

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology.

A genome-wide association study in more than 400,000 individuals identifies 139 new signals for lung function. These variants can predict chronic obstructive pulmonary disease in independent, transancestral cohorts.

A genome-wide association study suggests 41 previously unreported loci on top of the 23 known loci that influence the disease risk for lumbar disc herniations. Many of these loci harbour genes implicated in disc structure and inflammation, as well as genes related to the nervous system and nerve function.

Cognitive impairments are a key feature of psychopathology. Here, authors exploit the genetic overlap between cognitive dimensions and psychopathology to parse the biology of psychiatric illness and identify “meta-loci” genome segments characterized by specific patterns of overlap.

Gadd et al. identify proteins circulating in the blood that can stratify the risk people have of developing a range of leading age-related diseases, up to a decade before onset.

Genetic variation can influence levels of disease-related plasma proteins and, thus, contribute to the pathogenesis of complex diseases. Here, the authors perform genome-wide QTL analysis for 71 plasma proteins to identify causal proteins for coronary heart disease and provide a molecular QTL browser.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement.

Many genetic factors that contribute to uterine leiomyomata (UL) - the most common tumours of the female genital tract - remain to be discovered. Here, the authors conduct a UL meta-genome-wide association study, and find loci related to altered muscle tissue biology that are associated with UL.

Identifying women at high risk of breast cancer has important implications for screening. Here, the authors demonstrate that polygenic risk scores improve breast cancer risk prediction in the population, in women with mutations in high-risk genes and in women with close relatives with the disease.

The burden of mosaic chromosomal alterations in blood-derived DNA, a type of clonal hematopoiesis, is associated with an increased risk for diverse types of infections, including sepsis and pneumonia.

Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.

Mendelian randomization (MR) and colocalization analyses are used to estimate causal effects of 1,002 plasma proteins on 225 phenotypes. Evidence from drug developmental programs shows that target-indication pairs with MR and colocalization support were more likely to be approved, highlighting the value of this approach for prioritizing therapeutic targets.

Cardiovascular diseases (CVD) are associated with plasma lipid levels. Here, Tabassum et al. perform genome-wide association studies for lipidomic profiles with 141 (non-standard) lipid species which highlights shared genetic loci with CVD and that traditional lipids have low genetic correlation with other lipids.

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.