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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.

ZF5.3 is a mini-protein that escapes endosomes efficiently. Work to understand the underlying mechanism now reveals that ZF5.3 unfolds at pH values lower than 5.5 through protonation of Zn(II)-bound His residues. Unfolding promotes pH-dependent interactions with a unique lipid present in late endolysosomal membranes and is essential for endosomal escape.

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.

Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

Here the authors analyze de novo mutations in >10,000 parent-offspring trios and find that ancestry and smoking independently associate with mutation rate, but that common genetic variants likely contribute little to mutation rate variation.

An ideal method to construct azetidines would be through a [2 + 2] photocycloaddition that joins an olefin and an imine, shown only rarely in the literature, partially due to competitive photochemical processes of the imine. Here, the authors report copper-catalyzed photocycloadditions of imines and alkenes to produce a variety of substituted azetidines, via activation of the olefin.

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.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Estimates from the Global Dietary Database indicated that 2.2 million new type 2 diabetes and 1.2 million new cardiovascular disease cases were attributable to sugar-sweetened beverages worldwide in 2020, with the highest burdens in sub-Saharan Africa, Latin America and the Caribbean.

A CRISPR-Cas9 approach is used to perform saturating mutagenesis of the human and mouse BCL11A enhancers, producing a map that reveals critical regions and specific vulnerabilities; BCL11A enhancer disruption is validated by CRISPR-Cas9 as a therapeutic strategy for inducing fetal haemoglobin by applying it in both mice and primary human erythroblast cells.

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.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Recent estimates of sugar-sweetened beverages (SSBs) intake are generally unavailable. Here the authors show a global SSBs intake of 2.7 servings/week in 2018 in adults (range: 0.7 South Asia, 7.8 Latin America/Caribbean); intakes were higher among males, younger, more educated, and urban adults.

Cecilia Lindgren and colleagues report results of a large-scale genome-wide association study for waist-to-hip ratio, a measure of body fat distribution. They identify 13 new loci associated with this trait, several of which show stronger effects in women than in men.

Patricia Munroe, Joanna Howson and colleagues genotype ∼350,000 individuals and identify 30 new blood pressure– or hypertension-associated risk loci. Their analyses provide insights into the pathophysiology of hypertension and highlight new potential targets for clinical intervention.

This study examines the impact of herbivorous insects on biogeochemical cycling within forests. From a global network of 74 plots within 40 mature, undisturbed broadleaved forests, they show that background levels of insect herbivory are sufficiently large to alter both ecosystem element cycling and influence terrestrial carbon cycling.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

Engineering the tunability of protein assembly in response to pH changes within a narrow range is challenging. Here the authors report the de novo computational design of pH-responsive protein filaments that exhibit rapid, precise, tunable and reversible assembly and disassembly triggered by small pH changes.

An analysis based on data from the Global Dietary Database shows mean animal-sourced food intakes among children and adolescents increased modestly from 1990 to two portions per day in 2018, but remain low in sub-Saharan Africa, India and Bangladesh.

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.

Here the authors develop CRISPR–ChIP to enable the identification of factors required for chromatin regulation. Using this new method, they unveil a functional partitioning of H3K79 methylation into two distinct regulatory units, with important implications in MLL leukemia.

Modeling analysis from the Global Dietary Database estimated that 70% of new global cases of type 2 diabetes are attributable to suboptimal intake of 11 dietary factors, with substantial differences in dietary risks across world regions and nations.

Dietary quality is reported at the global, regional and national level across 185 countries. Though diet quality increased modestly since 1990 at the global level, in South Asia and Sub-Saharan Africa it did not improve. In some regions, children’s dietary quality is lower than that of adults.

A transancestral exome-wide association study for body-fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.

The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues.

The MAGIC investigators report results of a large genome-wide association study meta-analysis to identify common variants influencing fasting glucose homeostasis. They further show that several of the newly discovered loci influencing glycemic traits are also associated with risk of type 2 diabetes.

Private-investor approaches for measuring the emissions associated with lending to governments risk creating perverse incentives.

Single cell profiling of tissue from patients undergoing therapy has the potential to identify drug-induced immune changes. Here the authors show a skin scRNA-seq study of psoriasis patients treated with an IL-23 inhibitor and characterize changes in cell states during early treatment.

The molecular characterisation of germ cell tumours (GCT) is necessary to understand their development and histological diversification. Here, the authors use whole-genome and transcriptome sequencing of GCTs across distinct histologies to reveal their somatic evolution and clonal diversification, as well as identify several putative biomarkers for treatment stratification.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

Bioactive cements are widely used in dentistry and medicine. Here, using a variety of novel experimental techniques, the authors uncover the atomic and vibrational contributions to the mechanical toughness of bioactive cement during the setting process.

The Impact of Genomic Variation on Function Consortium is combining single-cell mapping, genomic perturbations and predictive modelling to investigate relationships between human genomic variation, genome function and phenotypes and will provide an open resource to the community.

Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk.

Loh et al. investigate the role of LRP5 mutations in adipose tissue biology. They demonstrate that LRP5 promotes lower-body fat distribution and enhances systemic and adipocyte insulin sensitivity, which suggests that pharmacological activation of LRP5 could prevent age-related fat redistribution and metabolic complications.

Using whole-genome data for single-nucleotide polymorphism and results from genome-wide association studies, the authors show that people’s preference for pairing with those with similar phenotypic traits has genetic causes and consequences.

Analysis of calcified dental plaque (calculus) specimens from Neanderthals shows marked regional differences in diet and microbiota and evidence of self-medication in one individual, and identifies prevalent microorganisms and their divergence between Neanderthals and modern humans.