Human Molecular Genetics

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 ...

Genome-wide association studies (GWAS) are conventionally conducted in cohorts spanning a wide age-range. These studies typically assume that genetic associations are constant across different ages. Some traits, however, may have age-varying genetic associations. This has implications for the interpretation of genetic effects derived in downstream applications, such as Mendelian randomization (MR) analyses. In this study we conducted a series of age-stratified GWAS on individuals aged 40-69 year...

Inflammatory bowel disease (IBD) frequently co-occurs with immune-mediated and metabolic disorders, but whether these associations reflect shared genetics or causal effects remains unclear. We performed two-sample Mendelian randomization (MR) using large-scale genome-wide association study (GWAS) summary statistics to investigate potential causal effects of immune-mediated diseases and lifestyle traits on IBD, Crohns disease (CD), and ulcerative colitis (UC). SNP-based heritability and genetic c...

Type 2 diabetes (T2D) is a genetically and clinically heterogeneous disorder influenced by metabolic, lifestyle, and cardiometabolic factors. Understanding the shared and distinct genetic architecture underlying T2D and its upstream risk traits is critical for improved risk prediction and stratified intervention. We applied genomic structural equation modeling (SEM) to genome-wide association study (GWAS) summary statistics for eight T2D-related phenotypes: gestational diabetes, hypertension, gl...

ObjectivesTo screen the entire genome for genes associated with risk for lateral epicondylopathy and improve understanding of underlying biological mechanisms and inform future research aimed at risk stratification and personalized prevention and treatment strategies. MethodsA genome-wide association study was conducted using UK Biobank data. Lateral epicondylopathy cases were identified based on electronic health records from individuals of European ancestry. Logistic regression tested associa...

Low-density lipoprotein cholesterol (LDL-C) is a well-established and modifiable risk factor for cardiovascular diseases (CVDs), which has been the leading cause of mortality among women and men in the United States since 1921. Despite research demonstrating sexually dimorphic symptom presentation of CVD, women remain underdiagnosed and undertreated for CVDs relative to men. Using genotype and phenotype data from the All of Us (AoU) Research Program, we examined sex-specific differences in LDL-C...

AimsNonsteroidal anti inflammatory drugs (NSAIDs) are a leading cause of drug hypersensitivity reactions (HRs), yet genetic determinants of individual susceptibility remain unclear. Growing evidence implicates oxidative stress in these reactions. This study aimed to identify genetic variants in redox and immune related pathways associated with cross reactive NSAID hypersensitivity (CR NSAIDs) and single NSAID induced urticaria/angioedema/anaphylaxis (SNIUAA), and to characterize their functional...

BackgroundGenetic risk scores (GRS) for type 1 diabetes (T1D) have been developed primarily in European populations, limiting their generalisability across ancestries. Indians differ from Europeans in clinical characteristics of T1D and overall genetic architecture, yet systematic evaluation of T1D GRS performance in multi-regional Indian cohorts is lacking. MethodsThe study included 597 T1D patients and 3347 non-diabetic controls from different regions in India. Genotyping, imputation, quality...

Microtia is a common congenital craniofacial malformation characterized by the partial or complete absence of the external ear structure. Despite its relatively high incidence, the pathogenesis of microtia remain poorly understood. In this study, we analyzed both single-cell and bulk RNA sequencing data from microtia cases and identified a population of COL1+HES1+ mesenchymal stem cell in perichondrium with significantly higher expression of the CRABP2 gene, a gene that encodes a nuclear transpo...

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...

AimsGestational diabetes mellitus (GDM) is the most common pregnancy-related medical complication. GDM is linked to aberrant immune responses in both mothers and offsprings, specifically, the subsequent development of inflammatory diseases. Whereas prior research has focused on specific immune cell subsets, a comprehensive overview of the impacts of GDM on maternal and fetal immune landscape is lacking. Here, we aim to comprehensively decipher how GDM modulates various immune cell populations in...

Type 2 diabetes (T2D) affects 11.1% of the global population, underscoring the need for biomarkers that inform treatment response and glycemic outcomes. We evaluated the association between the FTO variant rs9939609-A and glycemic control in a Mexican population. A total of 174 individuals living with T2D from Merida and Sisal, Yucatan, were included, of whom 85% were receiving oral hypoglycemic agents as main treatment. Glycemic control was defined cross-sectionally as good ([≤]130 mg/dL, n=...

Peripheral artery disease (PAD) is a global health burden affecting over 200 million individuals and is frequently complicated by limb-threatening ischemia, leading to major amputations. Despite known clinical risk factors, the genetic basis underlying amputation risk in PAD remains poorly defined. In this study, we performed a multi-pronged genome-wide association study (GWAS) to identify genetic variants associated with lower extremity amputation in patients with PAD, using data from the All o...

A substantial proportion of individuals with a well-defined monogenic disorder remain without a genetic diagnosis. Low-level mosaic pathogenic variants are increasingly recognised as an underappreciated cause of monogenic disease but are technically challenging to detect, particularly in organ-specific conditions when affected tissue is inaccessible. We systematically investigated low-level mosaic variants in individuals with congenital hyperinsulinism (CHI: n=1,252) or neonatal diabetes (NDM: n...

Polygenic risk scores (PRSs) are typically constructed under the assumption of a single, homogeneous disease phenotype. However, many common diseases exhibit considerable clinical heterogeneity and encompass multiple subtypes with distinct etiologies and clinical characteristics. As a result, conventional PRSs often overlook differences in underlying biological pathways among disease subtypes, consequently limiting predictive accuracy and cross-ancestry transferability. To address this challenge...

Somatic mutations and the tumor immune microenvironment in breast tumors are important predictors of treatment response and survival, yet data for Hispanic/Latina (H/L) women are limited. Here we analyzed whole exome sequencing data from tumor/normal pairs and RNAseq data from 748 H/L women and 388 non-Hispanic White (NHW) women. Overall, the somatic profiles in tumors from H/L women were similar to NHW women. However, somatic mutations in genome organizer CTCF were significantly more common in ...

Leber congenital amaurosis (LCA) and Early-onset severe retinal dystrophy (EOSRD) manifest within the first months and the first years of life, respectively. They are the leading cause of severe vision impairment in childhood. Using next generation sequencing, we identified eight families of patients with LCA/EOSRD carrying biallelic combination of six germline variants in DDX41, encoding a DEAD-box ATPase RNA helicase involved in RNA splicing, innate immunity and hematopoiesis. In fibroblasts f...

BACKGROUNDSoluble ST2 (sST2) predicts poor outcomes in heart failure (HF) and sepsis, but does it actually drive these conditions or just tag along for the ride? We used bidirectional Mendelian randomization (MR) to find out, testing six directional causal pathways among sST2, HF, and sepsis. METHODS AND RESULTSOur approach involved bidirectional two-sample Mendelian Randomization(MR) analyses drawing on genome-wide association study (GWAS) summary statistics: sST2 data came from deCODE Genetic...

Osteoporosis and fractures are major health concerns. We developed and validated a polygenic score (PGS) for osteoporosis in a Japanese population using heel quantitative ultrasound-derived T-scores. Genome-wide association study data from 12,371 participants in the Tohoku Medical Megabank Community-Based Cohort identified genome-wide significant loci, including MBL2, TMEM135, and WNT16. PGS models were constructed and evaluated using independent datasets for model selection (n = 1,419) and vali...

Rhabdomyolysis is the acute breakdown of skeletal muscle resulting from failure of cellular homeostasis in response to metabolic stress. Recurrent forms are frequently linked to inherited defects affecting energy metabolism or calcium handling. Ryanodine receptor type 3 (RyR3) is an intracellular calcium release channel, expressed in skeletal muscle, that contributes to the fine-tuning of calcium signaling. Although variants in other calcium-handling proteins have been implicated in rhabdomyolys...