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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.

Here the authors perform a trans expression quantitative trait locus meta-analysis study of over 3,700 people and link a USP18 variant to expression of 50 inflammation genes and lupus risk, highlighting how genetic regulation of immune responses drives autoimmune disease and informs new therapies.

Geospatial estimates of the prevalence of anemia in women of reproductive age across 82 low-income and middle-income countries reveals considerable heterogeneity and inequality at national and subnational levels, with few countries on track to meet the WHO Global Nutrition Targets by 2030.

Bhattacharjee and Schaeffer et al. map exclusive breastfeeding (EBF) in 94 low- and middle-income countries (LMICs), finding increased EBF practice and reduced subnational variation across the majority of LMICs from 2000 to 2018. However, only six LMICs will meet WHO’s target of ≥70% EBF by 2030 nationally, and only three will achieve this in all districts.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

A high-resolution, global atlas of mortality of children under five years of age between 2000 and 2017 highlights subnational geographical inequalities in the distribution, rates and absolute counts of child deaths by age.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent risk loci. Comparisons with other psychiatric disorders and candidate gene analyses provide new insights into major depressive disorder.

Gradual cooling or warming of the atmosphere, combined with strong ocean-driven basal melt, could have led to major changes in the periodicity, phasing, and asymmetry of past ice sheet growth and decay, according to an ensemble of 500-kyr long ice sheet simulations.

Fine-scale geospatial mapping of overweight and wasting (two components of the double burden of malnutrition) in 105 LMICs shows that overweight has increased from 5.2% in 2000 to 6.0% in children under 5 in 2017. Although overall wasting decreased over the same period, most countries are not on track to meet the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025.

MRI data from more than 100 studies have been aggregated to yield new insights about brain development and ageing, and create an interactive open resource for comparison of brain structures throughout the human lifespan, including those associated with neurological and psychiatric disorders.

Time-resolved crystallography (TRX) is used for monitoring only small conformational changes of biomacromolecules within the same lattice. Here, the authors report the interplay between synchronous molecular rearrangements and lattice phase transitions in RNA crystals, providing the basis for the investigation of large conformational changes using TRX.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Analyses of the proportions of individuals who have completed key levels of schooling across all low- and middle-income countries from 2000 to 2017 reveal inequalities across countries as well as within populations.

Associations of copy number variations (CNVs) with complex traits are challenging to study because of their low frequency. Here, the authors analyse SNP array and array comparative genomic hybridization data of 100,028 individuals and report their associations with immune-related, cardiometabolic and neuropsychiatric diseases as well as cancer.

Grant Stewart, Andrew Jackson, Christopher Mathew, Fowzan Alkuraya and colleagues identify a novel replication fork protein, DONSON, which is important for maintaining genome stability. Mutations in DONSON cause microcephalic dwarfism and lead to stalled replication forks and DNA damage.

Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

Massive clusters of galaxies have been found as early as 3.9 billion years after the Big Bang. Cosmological simulations predict that these systems should descend from 'protoclusters' — early overdensities of massive galaxies that merge hierarchically to form a cluster. Observational evidence for this picture, however, is sparse because high-redshift protoclusters are rare and difficult to observe. Here, a protocluster region 1 billion years (z = 5.3) after the Big Bang is reported. This cluster extends over >13 megaparsecs, contains a luminous quasar as well as a system rich in molecular gas. A lower limit of >4 × 10¹¹ solar masses of dark and luminous matter in this region is placed, consistent with that expected from cosmological simulations.

High-resolution subnational mapping of child growth failure indicators for 105 low- and middle-income countries between 2000 and 2017 shows that, despite considerable progress, substantial geographical inequalities still exist in some countries.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

Investigating malaria transmission at three sites in Uganda, the authors identify super-spreaders and show that super-spreading is more prominent at low-intensity transmission, and that seasonality and environmental stochasticity have a greater influence on super-spreading.

Autoimmune diseases are genetically complex disorders that affect up to 10% of the Western population. Here Li et al. quantify the heritability of a range of autoimmune diseases in the largest paediatric cohort examined to date, illustrating that genetic and non-genetic components variably contribute to the susceptibility of each disease.

Genome-wide association meta-analyses of waist-to-hip ratio adjusted for body mass index in more than 224,000 individuals identify 49 loci, 33 of which are new and many showing significant sexual dimorphism with a stronger effect in women; pathway analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution.

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

Andrew Morris, Mark McCarthy, Michael Boehnke and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes, including 26,488 cases and 83,964 controls from populations of European, east Asian, south Asian and Mexican and Mexican American ancestry. They identify seven loci newly associated with type 2 diabetes and examine the genetic architecture of disease across populations.

The genomes of filamentous fungi, such as Aspergillus, include many biosynthetic gene clusters of unknown function. Here, the authors show that copper starvation induces expression of an enzyme that generates a valine-derived isocyanide participating in two different pathways, for biosynthesis of acylated sugar alcohols and modified ergot alkaloids.

A meta-analysis across ten pediatric autoimmune diseases reveals shared genetic architecture and novel susceptibility loci.

Arabidopsiscontains multiple mediator proteins that function as transcriptional activators. Here, the authors show that MED18 has roles in plant immunity, control of flowering time and response to hormones, suggesting that mediator proteins control multiple pathways.

Young, star-forming galaxies can be characterized by their strong Lyman-α emission. An overdensity of such a population in one region of the sky is believed to mark a forming proto-cluster. An enhancement of submillimetre galaxies near the core of this proto-cluster, and a large-scale correlation between the submillimetre galaxies and the low-mass Lyman-a emitters suggests synchronous formation of the two different types of star-forming galaxies.

Margaret Goodell and colleagues report genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. They identify large regions of low methylation with borders marked by 5-hydroxymethylcytosine. These borders become eroded in the absence of DNA methyltransferase 3a.

Adélie penguins are a key Antarctic indicator species, but data patchiness has challenged efforts to link population dynamics to key drivers. Che-Castaldo et al. resolve this issue using a pan-Antarctic Bayesian model to infer missing data, and show that spatial aggregation leads to more robust inference regarding dynamics.

The One Thousand Plant Transcriptomes Initiative provides a robust phylogenomic framework for examining green plant evolution that comprises the transcriptomes and genomes of diverse species of green plants.

CD1 molecules present diverse lipid ligands to TCRs expressed by NKT cells. Rossjohn, Moody and colleagues show a unique form of autoreactivity with human CD1c molecules, whereby TCRs recognize a closed conformation of CD1c molecules, which are loaded with a diverse array of ‘headless’ glycolipids.

Femtosecond XFEL crystallography is used to identify dynamic changes in the adenine riboswitch aptamer domain, with at least four states identified in real time, two in the apo form before binding and two with the ligand bound.

Ketone bodies are elevated in response to fasting, a low-carbohydrate ketogenic diet or high-intensity exercise. Vishwa Deep Dixit and colleagues report that one metabolite, β-hydroxybutyrate, inhibits the NLRP3 inflammasome. In vivo, β-hydroxybutyrate is anti-inflammatory and suppresses NLRP3-mediated inflammatory disease.

This paper reports the detection of a high-redshift galaxy that may be more representative of ‘normal’ star-forming galaxies formed in the first billion years of the Universe than the extreme starbursts discovered to date.

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.

John Chambers and colleagues report a genome-wide association study for markers of liver function. They identify 42 loci associated with concentrations of one or more liver enzymes in plasma, and use a range of functional genomic analyses to suggest candidate genes at these loci.