Multi-Trait Polygenic Scores for COPD and COPD Exacerbations Implicate Druggable Proteins.

Objectives: To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting.

Design: Prospective cohort studies.

Setting: Genetic Epidemiology of COPD (COPDGene; 2007-present), Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE; 2005-2008), Mass General Brigham Biobank (MGBB; 2010-present), All of Us (2016-present), and UK Biobank (UKB; 2006-present).

Multi-ancestry polygenic risk scores for the prediction of type 2 diabetes and complications in diverse ancestries.

Background: Polygenic risk scores (PRSs) improve type 2 diabetes (T2D) prediction beyond clinical risk factors but perform poorly in non-European populations, where T2D burden is often higher, undermining their global clinical utility.

Methods: We conducted the largest global effort to date to harmonize T2D genome-wide association study (GWAS) meta-analyses across five ancestries-European (EUR), African/African American (AFR), Admixed American (AMR), South Asian (SAS), and East Asian (EAS)-including 360,000 T2D cases and 1·8 million controls (41% non-EUR). We constructed ancestry-specific and multi-ancestry PRSs in training datasets including 11,000 T2D cases and 32,000 controls, and validated their performance in independent datasets including 39,000 T2D cases and 126,000 controls of diverse ancestries.

BioNeuralNet: A Graph Neural Network based Multi-Omics Network Data Analysis Tool.

Multi-omics data offer unprecedented insights into complex biological systems, yet their high dimensionality, sparsity, and intricate interactions pose significant analytical challenges. Network-based approaches have advanced multi-omics research by effectively capturing biologically relevant relationships among molecular entities. While these methods are powerful for representing molecular interactions, there remains a need for tools specifically designed to effectively utilize these network representations across diverse downstream analyses.

Polygenic prediction of body mass index and obesity through the life course and across ancestries.

Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.

A multi-ethnic polygenic risk score for chronic kidney disease is associated with increased risk of hypertension in African American individuals.

Background: Hypertension (HT) and chronic kidney diseases (CKD) are complex conditions having both genetic and environmental contributions, disproportionately affecting African American (AA) individuals. Recent evidence is contradictory regarding the directionality of the relationship between the two conditions. This study investigates the relationship between CKD and blood pressure (BP)-related traits with CKD and BP by generating polygenic risk scores (PRSs) for CKD and BP-related traits in 2,995 AA participants of the Jackson Heart Study.

Ancestry Calibration of Polygenic Risk Scores Improves Risk Stratification and Effect Estimation in African American Adults.

Polygenic risk score (PRS) distributions vary across populations, complicating PRS risk assessment. We evaluated the impact of PRS calibration according to individualized genetic ancestry estimates on PRS performance using two large multi-ethnic PRS for type 2 diabetes (T2D) (PRS) and height (PRS), in 8,841 African American (AA) individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. We calibrated each participant's score as a function of estimated genetic similarity to the Yoruba (GSYRI) cohort in the 1000 Genomes Project.

Omic Risk Scores are Associated with COPD-related Traits Across Three Cohorts.

Background: Chronic obstructive pulmonary disease (COPD) exhibits marked heterogeneity in lung function decline, mortality, exacerbations, and other disease-related outcomes. Omic risk scores (ORS) estimate the cumulative contribution of omics, such as the transcriptome, proteome, and metabolome, to a particular trait. This study evaluates the predictive value of ORS for COPD-related traits in both smoking-enriched and general population cohorts.

Type 2 Diabetes Polygenic Risk Score Interactions with Lifestyle Risk Factors in Black Americans.

Introduction: Prior work in predominantly European ancestry populations has explained how the risk associated with demographic, lifestyle, and health factors differs with underlying genetic susceptibility to type 2 diabetes (T2D), but less is known about these relationships in Black Americans.

Methods: We used covariate-adjusted logistic regression models of T2D to examine interactions between a published trans-ancestry derived T2D polygenic risk score (PRS) and various demographic, lifestyle, and health-related factors among 28,251 self-identified Black Americans from six cohort studies.

Results: The results are generally consistent with prior work in White populations.

GLP-1R Polymorphisms Modify the Relationship Between Exposure to Gestational Diabetes Mellitus and Offspring BMI Growth: The EPOCH Study.

Objective: Exposure to maternal gestational diabetes mellitus (GDM) is associated with childhood BMI. Among youth, we explored whether three different glucagon-like peptide 1 receptor gene (GLP-1R) polymorphisms modified the associations between 1) GDM and BMI trajectories and 2) GDM and markers of glucose-insulin homeostasis.

Research Design And Methods: For 464 participants from the Exploring Perinatal Outcomes Among Children (EPOCH) study, microarray genotyping was performed during childhood (∼10 years).

Epigenome-wide DNA methylation association study of CHIP provides insight into perturbed gene regulation.

With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed CHIP. How these mutations result in increased risk for numerous age-related diseases remains poorly understood. We conduct a multiracial meta-analysis of EWAS of CHIP in the Framingham Heart Study, Jackson Heart Study, Cardiovascular Health Study, and Atherosclerosis Risk in Communities cohorts (N = 8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk.

Genome-wide association study and multi-ancestry meta-analysis identify common variants associated with carotid artery intima-media thickness.

Carotid artery intima-media thickness (cIMT) is a measurement of subclinical atherosclerosis that predicts future cardiovascular events, including stroke and myocardial infarction. Genome-wide association studies (GWAS) have identified only a fraction of the genetic variants associated with cIMT. We performed the largest GWAS for cIMT involving up to 131,000 individuals.

Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups.

Alterations in DNA Methylation, Proteomic, and Metabolomic Profiles in African Ancestry Populations with APOL1 Risk Alleles.

Key Points: We aimed to elucidate potential methylation, proteomic, and metabolomic mechanisms by which variants may be linked to kidney disease. We report distinct methylation profiling between risk allele carriers and noncarriers, many near gene family. We report higher APOL1 protein and lower C18:1 cholesteryl ester in two risk allele carriers.

Methylome-wide association analyses of lipids and modifying effects of behavioral factors in diverse race and ethnicity participants.

Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations.

Cross-Ancestry Comparison of Aptamer and Antibody Proteomics Measures.

Measures from affinity-proteomics platforms often correlate poorly, challenging interpretation of protein associations with genetic variants (pQTL) and phenotypes. Here, we examined 2,157 proteins measured on both SomaScan 7k and Olink Explore 3072 across 1,930 participants with genetic similarity to European, African, East Asian, and Admixed American ancestry references. Inter-platform correlation coefficients for these 2,157 proteins followed a bimodal distribution (median r=0.

Epigenome-wide association study meta-analysis of BMI in African American Adults.

Despite considerable advances in identifying risk factors for obesity development, there remains substantial gaps in our knowledge about its etiology. Variation in obesity (defined by BMI) is thought to be due in part to heritable factors; however, obesity-associated genetic variants only account for a small portion of heritability. Epigenetic regulation defined by genetic and/or environmental factors with changes in gene expression, may account for some of this "missing heritability".

GLP-1R Gene Polymorphisms and Metabolic Traits During Childhood and Adolescence: The EPOCH Study.

Context: This is the first study to examine the association between variants of the glucagon-like-peptide-1 receptor gene (GLP-1R) and metabolic characteristics among youth.

Objective: We explored separate associations of 3 GLP-1R polymorphisms (rs10305420, rs6923761, and rs1042044) with body mass index (BMI) trajectories and markers of glucose-insulin homeostasis.

Methods: Mixed models examined associations between GLP-1R polymorphisms and trajectories of BMI.

Identification of proteins associated with type 2 diabetes risk in diverse racial and ethnic populations.

Aims/hypothesis: Several studies have reported associations between specific proteins and type 2 diabetes risk in European populations. To better understand the role played by proteins in type 2 diabetes aetiology across diverse populations, we conducted a large proteome-wide association study using genetic instruments across four racial and ethnic groups: African; Asian; Hispanic/Latino; and European.

Methods: Genome and plasma proteome data from the Multi-Ethnic Study of Atherosclerosis (MESA) study involving 182 African, 69 Asian, 284 Hispanic/Latino and 409 European individuals residing in the USA were used to establish protein prediction models by using potentially associated cis- and trans-SNPs.