BMC Genomics

PurposeTo identify genetic variants associated with glucocorticoid (GC)-induced intraocular pressure (IOP) change using genome-wide association study (GWAS) and whole exome sequencing (WES) analyses. Methods530 participants from the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) trials were analyzed, with replication performed in an independent cohort of 588 participants from the Mass Eye and Ear/Retina Health Center (MEE/RHC). All participants were exposed to GC, primarily via intravi...

ImportanceGenome-wide association studies have identified hundreds of common single nucleotide polymorphisms (SNPs) and small insertions/deletions (indels) associated with primary open-angle glaucoma (POAG) risk, though these variants have modest effect sizes and individually may have minor contributions to disease development. As whole-genome sequencing data is becoming more readily available, structural variants and other complex genomic features can be interrogated for contribution to disease...

Primary open-angle glaucoma (POAG) disproportionately affects individuals of African ancestry, yet rare coding variation in this population remains understudied. To address this gap, we performed a multi-cohort exome-wide meta-analysis across POAAGG, PMBB, All of Us, and UK Biobank, including 4,815 POAG cases and 22,922 controls of genetically inferred African ancestry. Although no gene reached exome-wide significance, we identified several suggestive gene-level associations driven by rare varia...

BackgroundThe DES gene encodes the intermediate filament protein desmin, which connects different multi-protein complexes like the cardiac desmosomes and is highly important for the structural integrity of cardiomyocytes. Pathogenic DES-mutations cause filament assembly defects leading to cardiomyopathies. However, most DES-variants listed in genetic disease databases are currently classified as variants of unknown significance. Here, we functionally characterized 21 different DES-variants of un...

Glaucoma is the leading cause of irreversible blindness; vision loss is preventable with timely treatment, but early detection is challenging, leaving [~]50% undiagnosed, highlighting the need for improved risk assessment tools. We developed a polygenic risk score (PRS) using data from >6 million individuals. PRS performance was exceptional in European ancestries; top 10% PRS individuals had 10-fold increased risk (OR=10.0) relative to the remainder. Performance remained good across all major an...

We conducted the first genome-wide association meta-analyses of global and sectoral peripapillary retinal nerve fibre layer (pRNFL) thickness and Bruchs membrane opening-minimum rim width (BMO-MRW), the major optic nerve head structural and neurodegeneration biomarkers, including up to 25,942 and 12,080 participants, respectively, from the International Glaucoma Genetics Consortium. We identified 9 global pRNFL thickness and 9 global BMO-MRW loci, along with 28 and 19 loci for pRNFL and BMO-MRW ...

Predicting the pathogenic impact of missense variants is essential for understanding and diagnosing genetic diseases. These approaches have undergone significant evolution, with the latest methodologies based on deep learning approaches. Nonetheless, only a limited number use the potential of Protein Language Models (PLMs), which have demonstrated strong performance across various protein-related tasks. A new predictor, called PATHOS, was developed; it combines embeddings from an optimal set of...

IntroductionSequence-based typing (SBT) has been the standard molecular typing method for understanding Legionella pneumophila genetic relationships. However, genome-scale typing approaches, namely core-genome (cg) or whole-genome (wg) multilocus sequence typing (MLST), provide higher discriminatory power. To advance these capabilities, the Legionella International Typing (LIT) workgroup was established to develop, evaluate, and disseminate a novel cgMLST schema with enhanced wgMLST resolution f...

PurposeFuchs endothelial corneal dystrophy (FECD) is a common corneal disease and a leading indication for endothelial keratoplasty (EK). Although CTG18.1 repeat expansion is a major genetic risk factor, the contribution of polygenic background to disease progression remains unclear. We evaluated whether combining CTG18.1 expansion status with a FECD-specific polygenic risk score (PRS) enables genomic prediction of progression to EK. MethodsWe retrospectively analysed 589 individuals with FECD ...

Emerging infectious diseases often circulate undetected until they cause clinical illness, creating serious risks for public health and biosecurity. The U.S. blood supply, with millions of routinely collected and quality-controlled donations, offers an untapped national resource for proactive pathogen surveillance. We propose integrating metagenomic sequencing (MGS) into existing blood and plasma collection workflows to detect novel or unexpected viruses in deidentified residual samples. This ap...

BackgroundAortic stenosis (AS) and left ventricular diastolic dysfunction (LVDD) often coexist in heart failure (HF), but the mechanisms linking them remain unclear. While AS increases afterload and promotes myocardial stiffening, emerging AI-based evidence suggests LVDD can precede the development of AS or progress simultaneously, indicating shared upstream mechanobiological and inflammatory drivers. This study explores the genetic contributors connecting AS and LVDD to identify early molecular...

BackgroundThe hyperpolymorphic nature and structural complexity of the human leukocyte antigen (HLA) genomic region present challenges for accurate and scalable typing across diverse sample types. While wholegenome sequencing (WGS) offers the opportunity to infer HLA genotypes without targeted enrichment, systematic benchmarks across sequencing platforms, biospecimens and coverage levels remain limited. ResultsWe assembled a multi-platform resource of WGS datasets derived from short-read (Illum...

Household transmission of EV-D68 was identified in 35 of 1040 households (3.4%) in the Pacific Northwest between 2022-2024, with an estimated secondary attack rate of 15%. Sequences from within households clustered closely with 0 to 2 pairwise nucleotide differences (median 1) between cases 6-14 days apart (median 7).

Genomic surveillance of influenza viruses informs vaccine strain selection and evolutionary forecasting. Sequencing efforts vary widely across U.S. states, which raises concerns about spatial sampling bias. We evaluated how well 10,958 influenza virus genomes sampled by our group in Michigan captured the genetic diversity in 34,743 genomes circulating nationally from the 2021/22 through 2024/25 seasons. We defined seasonal hemagglutinin haplotypes and tracked their detection across states. A sma...

Pharmacogenomics is an essential component of precision medicine; however, most existing knowledge has been derived from populations of European ancestry, limiting the understanding of pharmacogenomic diversity in East Asian populations. In this study, we applied genotype imputation to the Korea Biobank Array v2.0 using a reference panel of 8,062 Korean whole-genome sequencing (WGS) samples and analyzed pharmacogenomic variants and phenotypes in 14,490 Korean individuals. To assess the accuracy ...

Functional interpretation is essential for understanding how genetic variants contribute to complex traits. Here, we identified and characterized regulatory variants in CD4+ T cells collected from 362 donors. We integrated molecular QTL mapping from single-cell RNA-seq profiles and chromatin accessibility with predicted variant effects from a deep learning model trained on chromatin accessibility data. We identified molecular features and transcription factor binding mechanisms underlying varian...

ObjectiveTo identify risk loci for Fuchs endothelial corneal dystrophy (FECD) and improve a genetic risk prediction model. DesignGenome-wide association study (GWAS), polygenic risk score (PRS) construction, and TCF4 CTG18.1 short tandem repeat (STR) length inference. ParticipantsThe study included 7,316 Europeans (EUR) with FECD or related corneal dystrophy phenotypes and 1,588,467 controls from the UK Biobank, All of Us, FinnGen, and the Million Veteran Program. Two independent EUR FECD coho...

Methods that analyze single-cell RNA-seq+ATAC-seq multiome data have shown promise in linking enhancers to target genes by correlating chromatin accessibility with gene expression across cells. However, correlations among ATAC-seq peaks may induce non-causal tagging peak-gene links (analogous to tagging associations in GWAS); indeed, we confirm that tagging effects induced by peak co-accessibility are pervasive in peak-gene linking. We defined two scores for each ATAC-seq peak: co-accessibility ...

We present a streamlined, solid-phase workflow for Oxford Nanopore sequencing that integrates DNA extraction, purification, and library preparation within a single microfluidic cartridge. By eliminating tube transfers and performing all enzymatic steps directly on captured DNA, the method minimizes sample loss, reduces hands-on time, and simplifies library generation for long-read sequencing. Starting from volumes as small as a single drop of blood, this integrated approach produces high-quality...

Detecting low variant allele fraction (VAF) mosaic variants without matching controls remains a major challenge in genomics, limited by technical noise, lack of benchmarks, and computational scalability. We present the DRAGEN mosaic caller, a hardware-accelerated approach identifying variants down to [~]1-2% VAF with low false-positive rates and hour-scale runtimes for mosaic SNV/indel detection from bulk sequencing. To support evaluation, we introduce a genome-wide low-VAF benchmark for variant...