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The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

From 2014–2017, marine heatwaves caused global mass coral bleaching, where the corals lose their symbiotic algae. The authors find, this event exceeded the severity of all prior global bleaching events in recorded history, with approximately half the world’s reefs bleaching and 15% experiencing substantial mortality.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

Microscopic imaging and biochemical studies show that sinuses in mouse and human form a highly dynamic surface that regulates fluid movement and immune cell surveillance via RAMP1-dependent regulation of smooth muscle contraction and RAMP2-dependent regulation of the sinus endothelial barrier.

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.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

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.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Together with a companion paper, molecular details of immune responses in a pig-to-human xenotransplantation are identified through dense longitudinal multi-omics profiling of the xenograft and the host recipient, across the 61-day procedure.

Ossenkoppele, Coomans and colleagues analyzed the tau PET data of 12,048 individuals from 42 cohorts worldwide. They found that age, amyloid-β status, presence of an APOE ε4 allele and female sex are key contributors to tau PET positivity, which should aid clinical decision-making and trial designs.

Around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus.

Here the authors identify TNIP1 as a risk factor for a fatal neurodegenerative disorder and discover specific genetic loci associated with the three main subtypes of this disorder. The findings highlight distinct disease mechanisms, emphasizing the roles of immunity and the notch signaling pathway.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

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.

Analyses of neuroimaging datasets from 5,306 participants across 15 countries found generally larger brain-age gaps in Latin American compared with non-Latin American populations, which were influenced by disparities in socioeconomic and health-related factors.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Kedzierska et al. report an association between low production of receptor-binding domain antibodies after mRNA vaccination and altered glycosylation of IgG before vaccination in people with comorbidities, and show that this condition disproportionately affects Australia’s First Nations peoples because of the high burden of comorbidities in this population.

It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk

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 experience sampling method (ESM) collects real-time reports of people’s feelings, actions, and surroundings, and originally included both numerical and open-ended responses. Whereas most studies today focus only on the numbers, we argue that open-ended responses should be collected and analyzed again, because they are essential for understanding what the numbers mean and for capturing context and the temporal order of experiences.

Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M⁺ diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.