Nature

The Genome Informed Risk Assessment (GIRA) report from eMERGE has become a standard approach to implement genomic precision medicine at scale. Here, we assess GIRAs utility and impact in a health care system independent of eMERGE, focusing on 9 adult conditions using the Penn Medicine Biobank (PMBB, n=48,279). We find a large number of patients - 50.1% (n=24,185) - were deemed by GIRA as high-risk for at least one of the 9 conditions with 30.4% (n=14,676) due to polygenic and/or monogenic risk. ...

BackgroundVariation in the HLA loci, located on human chromosome 6p, has been associated with hundreds of diseases and conditions. However, high levels of polymorphism that characterize the HLA system, coupled with generally modest effect sizes for most phenotypes, necessitate relatively large sample sizes to power association studies; meanwhile, high resolution HLA genotyping remains relatively resource intensive. These constraints limit identification of novel associations. While phenome-wide ...

India harbors one of the most complex demographic and genetic landscapes globally, comprising more than 4600 endogamous ethnolinguistic groups shaped by multiple waves of migration, prolonged isolation and deep social stratification. Odisha, an eastern state of India, is home to 62 indigenous tribal groups, including 13 Particularly Vulnerable Tribal Groups (PVTGs), many of which remain genetically understudied. These populations provide a unique opportunity to explore fine-scale population stru...

Haemorrhage is the leading preventable cause of trauma death, primarily through ischaemic consequences that current treatments cannot adequately address. We combined human transcriptomic data (n=458) with a controlled porcine model of haemorrhagic shock to identify treatment-responsive molecular mechanisms. Using latent factorisation, we prioritised distinct molecular signatures of the human shock response, including stress signalling, neutrophil activation, and cytotoxic lymphocyte programmes. ...

We report a previously undescribed genotypic configuration identified in twins with HNRNPU-related neurodevelopmental disorder. Both twins have two closely spaced mosaic variants on the same allele that never co-occur on any single DNA molecule, resulting in three distinct cell lineages within each individual. We define this genotypic configuration as clustered monoallelic mosaicism (cMoMa). Recognizing the extreme improbability of such a configuration, we systematically explore two potential me...

BackgroundClinical interpretation of LDLR, APOB, and PCSK9 variants is essential for diagnosing familial hypercholesterolemia (FH), yet manual evidence curation is labor-intensive and prone to variability. MethodsWe developed a web-based platform (https://fh-interpret.shinyapps.io/beta/) to automate the synthesis of multi-dimensional evidence. The tool integrates population frequencies (gnomAD), phenotype associations (UK Biobank), AI-based pathogenicity scores (AlphaMissense), high-throughput ...

Structural variants (SVs) are a major source of genomic diversity and disease susceptibility; however, populations from the Middle East and North Africa (MENA) region remain critically underrepresented in global reference databases. We provide the first detailed catalogue of structural variation in 61 individuals from diverse MENA countries, using publicly available ultra-long Oxford Nanopore sequencing. A scalable and dual-reference alignment-based method (GRCh38 and T2T-CHM13) was employed to ...

Mitochondria are semi-autonomous organelles whose generation and maintenance demand precise expression, processing, and assembly of >1,000 proteins encoded across two genomes. To explore this cooperativity, we performed multiomic analyses on >200 cell lines harboring mitochondrial gene perturbations, generating >26M molecular measurements. Our data reveal that mitochondrial proteome homeostasis is heavily influenced by post-transcriptional processes. Through nearest neighbor analyses, we reveal ...

Human genetics has become a cornerstone of drug target discovery, yet the value of Mendelian randomization (MR) for predicting clinical success remains uncertain. Here, we systematically evaluated MR across 11,482 target-indication pairs with documented Phase II clinical outcomes to assess its utility for drug development. We find that MR statistical significance alone does not enrich for Phase II success, in contrast to genome-wide association study (GWAS) support, which confers an increase in ...

BackgroundInfluenza vaccination and bacterial colonization both shape immunity in the respiratory tract, yet their combined impact on the human lung mucosa remains poorly understood. Secondary bacterial pneumonia following influenza infection is a leading cause of mortality, underscoring the need to define how vaccines and microbes intersect at the airway interface. MethodsUsing the Experimental Human Pneumococcal Challenge (EHPC) model, we examined how intramuscular inactivated (TIV) and nasal...

Why do some individuals develop mild COVID-19 while others progress to severe disease remains a central challenge in SARS-CoV-2 immunology. In this study, we leveraged the BACO Cohort - a unique historical cohort of immunologically naive, hospitalized COVID-19 patients from the first pandemic wave - to investigate early immune determinants of clinical disease trajectories. Integrating bulk RNA-seq, Olink proteomics, and systems serology, we identified two fundamentally distinct immune trajectori...

Cohesin is a fundamental genome-organizing complex that orchestrates three-dimensional chromosome folding and gene expression via DNA loop extrusion. Alterations to genes encoding cohesin subunits and cohesin loaders cause Mendelian disorders, including Cornelia de Lange syndrome (CdLS). By contrast, disruption of factors that remove cohesin from DNA, including WAPL and its binding partners PDS5A and PDS5B, have not yet been associated with human disease. Here, we explored the relevance of these...

Seasonality of inflammatory and infectious diseases is associated with several factors, including serum vitamin D fluctuations and immunological state. We longitudinally investigated peripheral blood mononuclear cell (PBMC) methylomes of healthy South African adults in summer, winter, and after high-dose winter vitamin D3 supplementation to determine whether vitamin D3 modulates seasonal epigenetic variations and whether these underpin reported seasonal transcriptional oscillations. PBMC DNA met...

TUBB2B encodes a {beta}-tubulin isotype essential for neuronal proliferation, migration, and organization during brain development. Pathogenic heterozygous variants in TUBB2B have been associated with a range of neurodevelopmental disorders, with phenotypes including polymicrogyria and corpus callosum abnormalities. However, the phenotypic spectrum remains heterogeneous, likely influenced by variant-specific effects on microtubule formation and stability, an area that warrants further investigat...

DNA Polymerase Delta (Pol {delta}) acts in DNA synthesis and in DNA repair, both important factors in the proliferative nature, longevity, and mutability of cancer cells. The chromosomal region containing POLD3, the third subunit of Pol {delta}, has recently been identified by genome wide-association studies as containing single nucleotide polymorphisms (SNPs) that increase the risk of colorectal cancer (CRC). Here, we have used genetic fine mapping and functional annotation tools to identify a...

BK polyomavirus (BKPyV) is a major complication in kidney transplant recipients (KTR), for whom no specific antiviral therapy is available. Modulation of immunosuppressive therapy results in virus clearance in most KTR with BKPyV DNAemia (controllers), but a significant minority fail to clear the virus (non-controllers). Here, we adapt LIBRA-seq, which links antibody sequence data to antigen specificity, to intact viral capsids of the four BKPyV genotypes to study and compare BKPyV-specific B-ce...

Early failure of antihypertensive medication treatment affects one in four patients, but the underlying mechanisms are poorly understood. We aimed to identify genetic determinants of antihypertensive treatment failure within the first year. Using longitudinal medication data from >400,000 genotyped antihypertensive medication users across 3 cohorts (FinnGen, the UK Biobank, and the Estonian Biobank), we classified short-term antihypertensive use trajectories as Continue, Switch, or Discontinue....

Linezolid is a critical last-resort antimicrobial for multidrug-resistant Enterococcus faecium, particularly against vancomycin-resistant lineages where therapeutic options are severely limited. While resistance has historically arisen through de novo chromosomal mutations, the global emergence of transferable resistance mechanisms threatens to render more infections untreatable. Here, we characterise a recent (2023-2024) hospital-associated outbreak of linezolid-resistant E. faecium in Queensla...

Transcription factors play key roles in cellular biology. Their genomic binding events are enriched at disease- and trait-associated genetic risk loci in particular cellular contexts. To examine this phenomenon in depth, we constructed a PU.1 (SPI1) binding atlas by uniformly processing 260 PU.1 ChIP-seq datasets spanning many immune cell types. Comparison of ChIP-seq peaks across eight major immune cell types identifies shared and cell type-specific PU.1 binding events. DNA sequence analyses re...

Population-based studies of circulating blood proteins have provided profound insights into human biology. However, short-lived changes often remained undetected. To address this, we performed a comprehensive longitudinal dried blood spot (DBS) self-sampling study in 808 young adults of the BAMSE cohort during 2020-2022. We profiled serological, autoimmune, and proteomic phenotypes in relation to SARS-CoV-2 exposures (infection, vaccination), physiological traits, genetic variation, and blood co...