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Discovering the genetic roots of diseases is a major question in genetic research. Here, the authors shed light on pleiotropy across diseases using a new method, scaled to millions of individuals, applied to single diseases and disease trajectories.

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

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

Genome-wide analyses identify variants associated with infertility and reproductive hormone levels but find limited polygenic overlap between reproductive hormone levels and infertility at the population level.

Intracytoplasmic sperm injection, usually reserved for cases of male infertility, was found to be nonsuperior to conventional in vitro fertilization in couples without male infertility concerns.

Glioblastoma is resistant to immune-checkpoint inhibitors. In this study, the authors report the results of an expansion cohort (n = 25) of a randomized testing neoadjuvant plus adjuvant pembrolizumab versus adjuvant pembrolizumab alone in patients with recurrent glioblastoma with resectable tumors.

Here the authors propose a crystal thermodynamics framework describing the tensor stress induced phase transformations in solids based on nonlinear elasticity and first principles calculations. The proposed approach enables balanced design of high-strength, high-ductility materials.

Genome-wide analyses using fetal and parental genotypes identify 40 independent associations influencing placental weight and highlight the role of the fetus in preeclampsia risk and placental growth regulation via insulin signaling.

Haue, Holm et al. use unsupervised clustering to subgroup a large set of ischemic heart disease patients from their pre-existing diseases, covering the entire multimorbidity spectrum. They identify subgroups that have different risk profiles and are characterized by different patterns when looking at patient blood tests and genetic profiles.

Meta-analyses of genome-wide association studies for endometriosis identify 49 distinct association signals. Fine-mapping of causal variants explores functional effects across various tissues. Genetic correlations between endometriosis and other pain conditions are also highlighted.

A European ancestry genome-wide meta-analysis of pregnancy-associated bleeding traits identifies five novel loci associated with postpartum hemorrhage, but none with early bleeding. Functional analysis highlights a role for progesterone receptor-mediated signaling.

A variant predicted to affect chromosome alignment in meiosis associates with intrachromosomal positioning of recombination and increases risk of detectable pregnancy loss by 22%, likely through missegregation of chromosomes.

The generation of a national pan-genome, a population-specific catalogue of genetic variation, may advance the impact of clinical genetics studies. Here the Besenbacher et al. carry out deep sequencing and de novo assembly of 10 parent–child trios to generate a Danish pan-genome that provides insight into structural variation, de novomutation rates and variant calling.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. Here, using genetic data for 1.52 million individuals, the authors identify 25 genes with protein-altering variants exhibiting a strong deficit of homozygosity, suggesting they are essential for successful early development.

Maternal genome-wide analyses identify variants associated with gestational duration and preterm delivery. Maternal alleles positively associated with gestational duration exhibit negative fetal effects on birth weight, likely reflecting antagonistic pleiotropy.

l-cysteine is required for the growth of Lactobacillus iners, a vaginal microbiome species typically associated with adverse outcomes that lacks cysteine biosynthesis pathways and key uptake mechanisms present in other lactobacilli. Cystine uptake inhibitors can be used to suppress L. iners abundance in vitro in favour of L. crispatus, a species associated with favourable outcomes.

Sex-stratified medicine is an important and understudied field. Here the authors investigate in a systematic study of the Danish population differences in incidence, risk, and several aspects of diagnoses between sexes and find differences across all areas of disease.

Genome-wide analysis of age at menopause under a recessive model identifies a stop-gain variant in CCDC201 associated with primary ovarian insufficiency. This homozygous genotype is present in 1 in 10,000 women of northern European ancestry.

Genome-wide association analyses of migraine and its subtypes identify new susceptibility loci, including rare variants with large effects implicating PRRT2, SCN11A and KCNK5.

A report of high-depth, short-read sequencing and de novo assemblies for 150 individuals from 50 parent–offspring trios as part of establishing a population reference genome for the GenomeDenmark project.

The largest meta-analysis of GWASs of hepcidin and sTfR identified 43 genomic loci, of which 15 new. Mendelian randomisation revealed associations of systemic iron status and iron-related loci with selected health outcomes across multiple domains.

In 2014, the Illuminating the Druggable Genome programme was launched to promote the exploration of currently understudied but potentially druggable proteins. This article discusses how the systematic collection and processing of a wide array of biological and chemical data as part of this programme has enabled the development of evidence-based criteria for tracking the target development level of human proteins, which indicates a substantial knowledge deficit for approximately one out of three proteins in the human proteome. It also highlights the nature of the unexplored therapeutic opportunities for major protein families.

Bell et al. report 46 new loci associated with biomarkers of iron homeostasis, including ferritin levels, iron binding capacity, and iron saturation, in the Icelandic, Danish and UK populations. The associated loci point to new iron-regulating proteins and important genetic differences between men and women.

GWAS meta-analysis associates 12 sequence variants with essential tremor, identifies seven candidate causal genes including CA3 with multiomics-based analysis, and reveals key roles of dopaminergic and GABAergic neurons in the pathogenesis.

Kjerulff et al. evaluate 47 biomarkers, including markers of inflammation and vascular stress, and their associations with demographic and lifestyle factors in healthy participants from the Danish Blood Donor study. Circulating biomarker levels varied according to sex, age, BMI and smoking status.