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The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

The next step after sequencing a genome is to figure out how the cell actually uses it as an instruction manual. A large international consortium has examined 1% of the genome for what part is transcribed, where proteins are bound, what the chromatin structure looks like, and how the sequence compares to that of other organisms.

Using the lifespan brain chart and two large-scale cross-cultural consortia (ABIDE and CABIC), we disentangle the heterogeneity of brain morphology in ASD into two structural impairment pathways that could disrupt sensory to association functions.

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

The ENIGMA-ORIGINs group presents a large and globally diverse pediatric neuroimaging dataset from birth to age 6. They use this resource to study the effects of sociodemographics and adverse birth outcomes on trajectories of brain volumes and cognition.

Most genetic studies have been done on European cohorts, which affects the efficacy of polygenic risk scores in non-European populations. Here, the authors demonstrate that a colorectal cancer PRS including Asian and European ancestries has improved performance over the European-centric PRS across racial and ethnic groups.

Halbrook et al. report two metabolic subgroups of pancreatic ductal adenocarcinoma cells defined by differential integrated stress response and asparagine production that permit symbiosis and phenformin resistance.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

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.

This Registered Report presents evidence from 87 countries and regions showing that brief emotion-regulation interventions consistently reduced negative emotions and increased positive emotions during the COVID-19 pandemic.

Patrick Sulem and colleagues report a genome-wide association study of age at menarche, finding and replicating an association with LIN28B. The authors test a number of variants previously associated with height and BMI and find that five loci previously associated with BMI are also associated with age at menarche.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Pulendran and colleagues delineated the mechanisms underlying the nonspecific antiviral effects exerted by the BCG vaccine against SARS-CoV-2 and reveal a pivotal role for BCG-specific CD4⁺ T cells that produce interferon-γ in imprinting a persistent antiviral innate program in the lung, mediating heterologous viral protection.

The role of the Nucleus Reuniens (NR)-CA1 pathway in contextual fear conditioning remains unknown. Here, the authors show that the NR-CA1 pathway transmits a signal that actively suppresses fear memory retrieval in CA1 during fearful behavior.

In this study, the authors provide a global overview of SARS-CoV-2 genome sequencing, and estimate the proportion of cases sequenced and time to genome upload. They identify disparities and highlight the need to strengthen surveillance in lower and middle income countries.

A multi-ancestry genome-wide association study meta-analysis, combined with transcriptome- and methylome-wide association analyses, identifies risk loci associated with colorectal cancer. Credible effector genes and their target tissues are also highlighted, showing that over a third probably act outside the colonic mucosa.

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.

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.

Two papers in this issue, by Bruns et al. and Zhao et al., show that megakaryocytes constitute a niche for hematopoietic stem cells in the mouse bone marrow and produce factors that regulate hematopoietic stem cell quiescence and proliferation.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

Herbert and colleagues show MrgprA3⁺ neurons activate myeloid cells to promote cutaneous IL-17-dependent immunity against Schistosoma mansoni.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

Multi-ancestry genome-wide association meta-analysis of major depression identifies new risk loci, assesses the transferability of risk loci across ancestry groups, and improves fine-mapping resolution and prioritization of candidate effector genes.

The heterogeneity of whole-exome sequencing (WES) data generation methods presents a challenge to joint analysis. Here, the authors present a bioinformatics strategy to generate high-quality data from processing diversely generated WES samples, as applied in the Alzheimer’s Disease Sequencing Project.

Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.

Trans-ethnic analyses of exome array data identify new risk loci for type 2 diabetes. Fine-mapping analyses using genome-wide association data show that the index coding variants represent the likely causal variants at only a subset of these loci.

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.

Solid organ transplant recipients are at increased risk of infectious disease and have unique molecular pathophysiology. Here the authors use host-microbe profiling to assess SARS-CoV-2 infection and immunity in solid organ transplant recipients, showing enhanced viral abundance, impaired clearance, and increased expression of innate immunity genes.

Patricia Munroe, Christopher Newton-Cheh, Andrew Morris and colleagues perform association studies in over 340,000 individuals of European ancestry and identify 66 loci, of which 17 are novel, involved in blood pressure regulation. The risk SNPs are enriched for cis-regulatory elements, particularly in vascular endothelial cells.

Most confirmed susceptibility variants for epithelial ovarian cancer lie in non-protein-coding sequences. Here Permuth-Wey and colleagues investigate variants in 3′ untranslated regions (UTRs) and uncover a new susceptibility locus.

Ken Ong and colleagues report meta-analysis of 32 genome-wide association studies for age at menarche. They identify 30 loci newly associated with age at menarche, including four that were previously associated with BMI.

Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.

MetaSTAAR enables functionally informed rare variant association analysis in biobank-scale cohorts using an efficient, sparse matrix approach for summary statistic storage.

A transcriptome-wide association study identifies associations of genetically predicted gene expression with breast cancer risk. This analysis finds 48 candidate genes implicated in breast cancer susceptibility, including 14 at novel loci.

High resolution combined confocal and two-photon video imaging of individual haematopoietic cells is performed in the bone marrow of living animals, examining their relationship to blood vessels, osteoblasts and endosteal surface as they home and engraft. It is found that osteoblasts were enmeshed in microvessals and different populations of haematopoeitic cells were localized in different areas according to their stage of differentiation. In settings of engraftment as well as expansion, marrow stem/progenitor cells were in closer proximity to bone and osteoblasts.

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.