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Kathryn Lunetta and colleagues report a meta-analysis of 22 genome-wide association studies for age at menopause. They identify 13 loci newly associated with age at natural menopause, including several candidate genes with roles in DNA repair and immune function.

The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.

The BIN1 SNP rs744373 is associated with higher CSF tau and phosphorylated tau levels. Here the authors show, using PET imaging, that this SNP is associated with tau accumulation in the brain as well as impaired memory in older individuals without dementia.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

Patient-derived xenografts are important tools for cancer drug development. Here, the authors develop models from 22 non-small cell lung cancer patients. They show genomic differences between models created from different spatial regions of tumours and a bottleneck on model establishment.

Tau accumulation is associated with disease progression in Alzheimer’s disease. Here the authors use resting state fMRI and tau-PET to demonstrate that baseline connectivity in Alzheimer's disease is associated with tau spreading.

A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.

This work shows that treatments used for acute myeloid leukaemia and targeted therapies could be used for early T-cell precursor acute lymphoblastic leukaemia.

Whether Alzheimer’s disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

Analyses of height and body mass index in 119,000 sibling pairs show that linkage and genome-wide association signals colocalize. Further analyses suggest that family-based linkage signals are fully consistent with a highly polygenic architecture.

This paper identified >500 genetic loci associated with behaviors and disorders related to self-regulation, including addiction and child behavior problems. The resulting genetic risk scores predict several behavioral, medical and social outcomes.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

Small-angle X-ray scattering and crystal structures of the PA28 proteasome regulator from Plasmodium falciparum, combined with cryo-electron microscopy structures of the 20S proteasome in complex with these regulatory PA28 proteins and molecular dynamics simulations, elucidate the regulatory mechanisms of parasite proteasome degradation.

Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.

Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution.

A glue ingredient was the secret to getting the mouse cells to multiply outside the body.

Here authors show that machine learning derives the degree of background retinal pigmentation with more nuance than self-described ethnicity. Retinal pigment scores are associated with genes linked to melanin and may improve algorithmic fairness.

Three studies identify a transcription-coupled DNA–protein crosslink repair pathway that depends on the Cockayne syndrome proteins and the proteasome.

APOE is the major genetic risk factor for Alzheimer’s disease. In a large number of neuropathologically confirmed cases and controls, the impact of different APOE genotypes on Alzheimer’s dementia risk was greater than previously thought and APOE2 homozygotes had an exceptionally low risk.

Brain-iron elevation is implicated in Alzheimer’s disease (AD), but the impact of the metal on disease outcomes has not been analysed in a longitudinal study. Here, the authors examine the association between the levels of ferritin, an iron storage protein, in the cerebrospinal fluid (CSF) of AD patients and show that CSF ferritin levels predict AD outcomes.

A meta-analysis of genome-wide association studies in more than 66,000 individuals identifies 68 new genomic loci that reliably associate with platelet count and volume, and reveals new gene functions.

Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.

Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Integration of GWAS and single-cell transcriptomic data from the entire nervous system systematically identifies cell types underlying brain complex traits and provides insights into the etiology of Parkinson’s disease.

Previous work has identified several genes where mutations lead to breast cancer, but other genetic and environmental factors must still be accounted for. A large study of genetic association with breast cancer points to four novel genes and many more genetic markers that should be pursued for their link to cancer susceptibility.

Metagenomic analyses of European pig and poultry farms show differing resistome profiles and an association with country-level antibiotic use.

Paul Thompson and colleagues report a genome-wide association study for hippocampal, intracranial and total brain volume. They identify a locus at 12q24 associated with hippocampal volume and a locus at 12q14 associated with intracranial volume.

New antimalarials are urgently needed. Here, the authors identify Open Source Malaria compound, OSMS-106, as a reaction hijacking inhibitor of the malaria parasite protein synthesis machinery, with potential use for treatment and prophylaxis.

Mammalian genomes are scattered with repetitive sequences, but their biology remains largely elusive. Here, the authors show that transcription can initiate from short tandem repetitive sequences, and that genetic variants linked to human diseases are preferentially found at repeats with high transcription initiation level.

The heterochromatic 'condensates' may not be conserved across mammals. This study highlights the influence of host genome on nuclear architecture and challenges the hypothesis that heterochromatin and MeCP2 undergo phase separation.

The lineage-specific receptor CSF1R controls macrophage development and homeostasis. Here the authors show that deletion of a conserved Csf1r enhancer (FIRE) selectively depletes brain microglia and resident macrophages in the epidermis, kidney, heart and peritoneum of otherwise healthy mice.

The FANTOM4 study identified transcriptional start sites active during proliferation arrest and differentiation of the human monocytic cell line THP-1. Systematic knockdown of 52 transcription factors provide support for their model in which a complex transcriptional network regulates the differentiation process.

The authors describe a huge submarine landslide deposit offshore Tanzania and highlight that large and potentially tsunamigenic landslide events are associated with plateau uplift and continental rifting in East Africa.

Using a sample of more than 1 million individuals, Hatoum et al. identify genomic loci associated with general and substance-specific addiction risk.

The ‘pace of life’ depends on both metabolic rate and life history traits; however, whether these evolve similarly in response to the environment is not clear. Here, Auer et al. show parallel evolution of metabolic rate and a suite of life history traits in response to predator environment in Trinidadian guppies.

This Resource presents an atlas classifying the age-related changes in human hematopoietic stem and progenitor cells from gestation through aging.