PLOS Genetics

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 ...

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...

Age-related hearing loss (ARHL) is a progressive, bilateral decline in hearing ability that affects one in four individuals over 60 years of age worldwide. While previous genome-wide association studies (GWAS) have identified distinct single-nucleotide variants (SNVs) associated with metabolic and sensory ARHL phenotypes, the contribution of short tandem repeats (STRs) - a neglected yet important class of genetic variants - remains poorly understood. To address this gap, TRTools was used to impu...

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...

Menieres disease (MD) is a chronic inner ear disorder characterized by recurrent vertigo, fluctuating sensorineural hearing loss, and tinnitus. Despite these distinctive symptoms, its etiology remains poorly understood. We performed a genome-wide meta-analysis of 8,969 cases and 1,962,542 controls across five large biobanks, identifying five independent genome-wide significant loci and estimating an observed-scale SNP heritability of 7% (SE 0.8%), consistent with a modest but significant genetic...

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...

Mapping the pleiotropic effect of genetic variation on biological processes and complex phenotypes is fundamental to extracting translational insight from genome-wide association studies (GWAS). Here we present The Human Genotype-Phenotype Map (GPMap), a repository of colocalizing genetic associations across 15,997 complex traits and 2.7 million molecular measurements, leveraging common and rare variants and cis-and trans-acting effects across disaggregated tissue types and single cell datasets ...

Genome-wide association studies (GWAS) have implicated tens of thousands of genetic variants associated with complex traits and polygenic diseases. Colocalizing GWAS variants with variants that may regulate gene expression, via expression quantitative trait loci (eQTL) mapping, has successfully led to the identification of disease-critical genes and their cell types of action. Recent studies predominantly colocalize proximal cis-eQTLs, which are estimated to regulate [~]10% of variance in gene e...

Electronic health records (EHRs) have become the cornerstone of population-scale genetic studies1, but factors including patterns of healthcare use shape which and how diagnoses are recorded, leading to confounding effects in genetic associations with EHR codes2. In this study we propose EDGAR, a deep learning framework that recovers lifetime disease liability from EHR by aligning diagnostic codes with clinically validated measures and disease labels in a set of individuals prioritized through a...

The Clinical Pharmacogenetics Implementation Consortium (CPIC) bases its drug-gene recommendations on the assignment of star alleles, which map known genotypes to defined functional categories and corresponding drug dosage guidelines. The star allele framework, first proposed in 1996 for the CYP gene family and later formalized with CPICs establishment in 2010 [1, 2], remains foundational to pharmacogenomics. However, this system has notable limitations. Its dependence on a restricted set of ben...

Lipoedema is a chronic adipose tissue disorder mainly affecting women with excess subcutaneous fat deposition on the lower limbs, associated with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is not well studied. We conducted a genome-wide association study (GWAS) for this disorder in a clinically ascertained cohort from Spain and performed a meta-analysis with the UK lipoedema cohort GWAS. We then used the result...

Polygenic scores (PGS) have emerged as an important tool for genetic risk prediction in medicine to identify individuals at high-risk for disease. A major limitation in their implementation is the apparent disagreement among scores for the same individual decreasing their interpretability and utility in clinical settings. Here we show that the poor agreement across PGSes for type 2 diabetes (T2D) is fully explained by statistical uncertainty in PGS-based prediction; individual-level uncertainty ...

In a recent article in Science, Shenhar et al. report that human life span heritability reaches [~]55% after removing "extrinsic" mortality, roughly seven-fold higher than recent large pedigree estimates. This conclusion rests on classifying deaths from infections and accidents as environmental noise independent of genetics. This premise is biologically untenable: susceptibility to severe infection is substantially heritable, with adoptee studies showing relative risks exceeding 5 for infection ...

Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part o...

Trade-offs form a key constraint in many aspects of organismal evolution, though they may help maintain genetic diversity. Late-onset Alzheimers disease (LOAD) shows features in common with the male-female health survival paradox: females suffer from higher prevalence and risk, as well as faster rates of cognitive decline while males suffer higher mortality. Though antagonistic pleiotropy could explain the tendency of LOAD to appear late in life, the sexually dimorphic profile suggests a role fo...

Polygenic risk scores (PRSs) have emerged as a valuable tool for genetic risk prediction and stratification in human diseases. Over the past decade, extensive methodological efforts have focused on improving the predictive power of PRS, leading to the development of numerous methods for PRS construction. Benchmarking these various methods thus becomes an essential task that is crucial for guiding future PRS applications. While studies have benchmarked subsets of these methods on specific phenoty...

Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes mellitus. Although sleep duration may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. In the present study, we conducted genome-wide gene by sleep duration meta-analyses, separately assessing interactions of short and long sleep, for fasting glucose, fasting insulin, and hemoglobin A1c ...

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. ...

Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of pediatric kidney failure, yet the genetic etiologies remain elusive for most affected individuals. Reanalysis of trio exome sequencing data from 80 Chinese CAKUT patients identified 32 rare, predicted deleterious variants. Replication in unrelated families from a national multicenter database prioritized four novel candidate genes--DOCK11, MIB1, TENM2, and TNS1. These candidates are involved in both well-charac...

Low-frequency variants (LFVs), defined by minor allele frequencies (MAF) of 1-5%, occupy the gap between common and rare variants in both frequency and effect size. The conventional genome-wide association study (GWAS) significance threshold (5x10-) is overly conservative for LFVs, which account for more than 25% of variants in GWAS. This limitation may obscure meaningful associations in highly heritable yet genetically complex disorders such as autism spectrum disorder (ASD). We hypothesize tha...