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.

The Circulating Lipidome In Severe Obesity.

Background: Severe obesity (SevO; BMI ≥40 kg/m) is rapidly increasing globally and disproportionately affects minority populations. However, it remains understudied in mechanistic and omics literature. Lipid metabolism plays a central role in obesity-related cardiometabolic disease (CMD), but the relationship between molecular lipid species and SevO is poorly understood, particularly in high-risk groups.

Multi-omics of human obesity and related multi-system diseases.

Context: Efforts to characterize the shared molecular risk factors that contribute to obesity and the downstream disease sequelae it triggers have been limited.

Objective: We aimed to identify functional genes with evidence for both causal and consequential effects on obesity related traits and their downstream sequalae using integrated genomic and proteomic data.

Methods: We investigated the association of obesity related traits with 2,912 plasma proteins in 259 individuals from the Cameron County Hispanic Cohort (CCHC) with validation of results in ∼45,000 participants from UK Biobank (UKBB).

Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.

Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids.

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.

The contribution of gametic phase disequilibrium to the heritability of complex traits.

Nonrandom mating induces genome-wide correlations between unlinked genetic variants, known as gametic phase disequilibrium (GPD), whose contribution to heritability remains uncharacterized. Here we introduce the disequilibrium genome-based restricted maximum likelihood (DGREML) method to simultaneously quantify the additive contribution of SNPs to heritability and that of their directional covariances. We applied DGREML to 26 phenotypes of 550,000 individuals from diverse biobanks and found that cross-autosome GPD contributes 10-27% of the SNP-based heritability of height, educational attainment, intelligence, income, self-rated health status and sedentary behaviors.

Genetic ancestry influences gene-environment interactions with sociocultural factors: Results from the Hispanic Community Health Study/Study of Latinos.

Often, studies will aggregate all participants identified as Hispanic/Latino, despite genetic and environmental substructures, preventing the meaningful interrogation of the roles of genetics and environment in human health. Using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we examined how self-identified background group and genetic ancestry influence gene-environment interactions between body mass index (BMI) and a polygenic score for BMI (PGS). Participants (n = 7,075) identified with six background groups: Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American.

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.

Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits.

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (n = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping.

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.

A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes.

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.

Multiomics reveal key inflammatory drivers of severe obesity: IL4R, LILRA5, and OSM.

Polygenic severe obesity (body mass index [BMI] ≥40 kg/m) has increased, especially in Hispanic/Latino populations, yet we know little about the underlying mechanistic pathways. We analyzed whole-blood multiomics data to identify genes differentially regulated in severe obesity in Mexican Americans from the Cameron County Hispanic Cohort. Our RNA sequencing analysis identified 124 genes significantly differentially expressed between severe obesity cases (BMI ≥40 kg/m) and controls (BMI <25 kg/m); 33% replicated in an independent sample from the same population.

Type 2 diabetes polygenic risk score demonstrates context-dependent effects and associations with type 2 diabetes-related risk factors and complications across diverse populations.

Polygenic risk scores (PRS) hold prognostic value for identifying individuals at higher risk of type 2 diabetes (T2D). However, further characterization is needed to understand the generalizability of T2D PRS in diverse populations across various contexts. We characterized a multi-ancestry T2D PRS among 244,637 cases and 637,891 controls across eight populations from the Population Architecture Genomics and Epidemiology (PAGE) Study and 13 additional biobanks and cohorts.

A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations.

Background: Gene-environment interactions may enhance our understanding of hypertension. Our previous study highlighted the importance of considering psychosocial factors in gene discovery for blood pressure (BP) but was limited in statistical power and population diversity. To address these challenges, we conducted a multi-population genome-wide association study (GWAS) of BP accounting for gene-depressive symptomatology (DEPR) interactions in a larger and more diverse sample.

Trans-ancestry genome-wide association study of childhood body mass index identifies novel loci and age-specific effects.

Over the past 30 years, obesity prevalence has markedly increased globally, including among children. Although genome-wide association studies (GWASs) have identified over 1,000 genetic loci associated with obesity-related traits in adults, the genetic architecture of childhood obesity is less well characterized. Moreover, most childhood obesity GWASs have been restricted to severely obese children, in relatively small sample sizes, and in primarily European-ancestry populations.

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".

Influence of Genetic Ancestry on Gene-Environment Interactions of Polygenic Risk and Sociocultural Factors: Results from the Hispanic Community Health Study/Study of Latinos.

Background: Many present analyses of Hispanic/Latino populations in epidemiologic research aggregate all members of this ethnic group, despite immense diversity in genetic backgrounds, environment, and culture between and across Hispanic/Latino background groups. Using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we examined the role of self-identified background group and genetic ancestry proportions in gene-environment interactions influencing the relationship between body mass index (BMI) and a polygenic score for BMI (PGS).

Methods: Weighted univariate and multivariable generalized linear models were executed to compare the effects of environmental variables identified by McArdle et al.

Multivariable Mendelian randomization with incomplete measurements on the exposure variables in the Hispanic Community Health Study/Study of Latinos.

Multivariable Mendelian randomization allows simultaneous estimation of direct causal effects of multiple exposure variables on an outcome. When the exposure variables of interest are quantitative omic features, obtaining complete data can be economically and technically challenging: the measurement cost is high, and the measurement devices may have inherent detection limits. In this paper, we propose a valid and efficient method to handle unmeasured and undetectable values of the exposure variables in a one-sample multivariable Mendelian randomization analysis with individual-level data.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways.