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The impact of variants of uncertain significance (VUS) on protein function and cancer risk remain unclear. Here, the authors focus on the functional impact of VUS of the PALB2 gene and identify defects in DNA damage repair by homologous recombination associated with increased risk of breast cancer.

Genetic variants of TREX1, a negative regulator of type I interferon responses, have been linked previously to non-monogenic systemic lupus erythematosus (SLE). Here the authors analyze UK Biobank multi-omics data to show that, while a derived oligoprotein interferon signature associates with increased SLE risk, TREX1 variants do not.

Lowering the levels of coagulation factor XII may prevent thrombosis without increasing the risk of bleeding. Here, Haj et al. use a large human dataset to show that this is the case for people carrying mutations that lower the levels of factor XII.

Authors use metagenomic environmental surveillance in Cambodian live-bird markets and found that air sampling captured the greatest diversity of poultry viruses. It outperformed traditional swabs, identifying undetected H5N1 clades.

The role of structural variants (SVs) in Mycobacterium tuberculosis has been understudied. In this study, the authors leverage 859 high-quality, diverse, long-read assemblies to construct pangenome reference graphs (PRGs).

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

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.

Marine darkwaves can be used to compare patterns and ecological consequences of episodic light reduction in marine ecosystems, according to application of the framework to both in situ and satellite based light irradiance data from California and New Zealand.

Central serous chorioretinopathy is an eye disease whose etiology is not well known. Here, the authors performed genetic association studies and identified vascular endothelial protein tyrosine phosphatase (VE-PTP) as a likely regulator of the risk of central serous chorioretinopathy, as well as other eye and vascular diseases.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

This study demonstrates that the co-occurrence of two specific variants in the TYR and OCA2 genes significantly increases the likelihood of having albinism. The outlined approach could help to elucidate digenic/oligogenic patterns in other rare conditions.

The Taiwan Precision Medicine Initiative (TPMI) has built a cohort of more than half a million individuals with Han Chinese ancestry, providing a rich resource of genetic and medical data for this group.

A rare variant burden analytical framework for Mendelian diseases was developed and applied to data from the 100,000 Genomes Project, identifying 69 probable new disease–gene associations.

Primary angle-closure glaucoma can cause blindness. Here, the authors study populations of Asian and European ancestries and find that genetic factors associated with darker irises and being far sighted increase the risk of developing the condition.

Exome-sequencing analyses of a large cohort of patients with type 2 diabetes and control individuals without diabetes from five ancestries are used to identify gene-level associations of rare variants that are associated with type 2 diabetes.

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.

DNA sequencing of 3,864 individuals with ALS and 7,839 controls identified a novel disease gene, DNAJC7, which encodes a heat-shock protein. As DNAJC7 is an essential part of cell maintenance, mutations in DNAJC7 may lead to neurodegeneration.

The severity of rare genetic diseases often varies between individuals, but small sample sizes make it difficult to identify contributing factors. Here, the authors use biobank-scale clinical and genetic data to investigate a role for common genetic variation.

A cross-ancestry genome-wide association meta-analysis of lung cancer including 61,047 cases and 947,237 controls identifies five new cross-ancestry susceptibility loci and highlights ancestry-specific effects of common and rare variants on lung cancer risk.

Khetarpal et al. show that the metabolic regulator PGC-1α is essential in heart muscle cells for exercise-driven cardiac growth, and that suppression of the stress-induced myokine GDF15 is required to enable cardiomyocyte adaptations to training.

Gene-based rare variant analyses for 601 diseases across 748,879 individuals from three biobanks identify 363 significant associations and highlight important considerations for multi-ancestry and cross-biobank sequencing studies.

The relationship between pathogenic germline variation, clonal hematopoiesis (CH) and risk of hematologic malignancy is explored in 731,835 individuals across 6 cohorts. Carriers of variants in certain genes show distinct patterns of CH and increased risk of CH progression to malignancy.

Neil Burns et al. use a continuous-surface otolith microchemistry approach to geolocate whiting across the west coast of the UK and show connectivity across existing stock boundaries, highlighting the importance of the Firth of Clyde nursery area. This study is important for fisheries management and will have an influence on methods used to infer connectivity from otolith microchemistry.

The authors introduce a cost-efficient, non-additive genome-wide association study pipeline that, when applied to a dominant analysis of 2329 phenotypes in 500,349 individuals, reduced computational costs from $27,000 to $39 and identified 781 new associations.

Analysis of exome sequencing data identifies a missense variant in RAB32 associated with high risk of familial Parkinson’s disease. Functional studies show that this risk variant increases LRRK2 kinase activity.

In individuals with obesity and compensated metabolic dysfunction-associated steatohepatitis-related cirrhosis, metabolic surgery was associated with a lower risk of major adverse liver outcomes, compared with nonsurgical management.

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.

Here the authors analyse rare coding variants to identify schizophrenia risk genes. Associations are reported at exome-wide significance for STAG1 and ZNF136, and at a false discovery rate of 5% for SLC6A1, PCLO, ZMYND11, BSCL2, KLC1 and CGREF1.

Comprehensive genomic and transcriptomics analyses of more than 1,300 cases of childhood T-lineage acute lymphoblastic leukaemia identify 15 distinct subtypes that are associated with specific outcomes.

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.

Albinism is a rare disorder often caused by high-effect rare variants in the TYR gene. Here, the authors study a large albinism cohort and find that a common variant in the TYR promoter contributes to albinism by modifying the penetrance of other common variants, demonstrating a complex genetic architecture.

Exome sequence data from 628,388 individuals was used to identify 24 risk loci in 40,208 carriers of clonal haematopoiesis of indeterminate potential and link them to other conditions including COVID-19, cardiovascular disease and cancer.

African Americans have an elevated risk of developing chronic kidney disease, yet only a fraction of those with high-risk genotypes develop the disease. Here, the authors show that a missense variant in APOL1 has a strong protective effect when co-inherited with the high-risk G2 allele of APOL1, with important implications for clinical practice and translational research.

Rare variant analyses identify a new type 2 diabetes risk allele near the LEP gene, which encodes leptin, and other risk alleles of intermediate penetrance in genes previously implicated in monogenic forms of diabetes.

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.

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.

Genome-wide association analyses comprising 14,256 cases and 1,199,156 controls and incorporating correlated cardiac magnetic resonance imaging traits provide insights into the molecular etiology of dilated cardiomyopathy.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.