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Translational Psychiatry Jan 2024Tobacco use is a major risk factor for many diseases and is heavily influenced by environmental factors with significant underlying genetic contributions. Here, we... (Meta-Analysis)
Meta-Analysis
Tobacco use is a major risk factor for many diseases and is heavily influenced by environmental factors with significant underlying genetic contributions. Here, we evaluated the predictive performance, risk stratification, and potential systemic health effects of tobacco use disorder (TUD) predisposing germline variants using a European- ancestry-derived polygenic score (PGS) in 24,202 participants from the multi-ancestry, hospital-based UCLA ATLAS biobank. Among genetically inferred ancestry groups (GIAs), TUD-PGS was significantly associated with TUD in European American (EA) (OR: 1.20, CI: [1.16, 1.24]), Hispanic/Latin American (HL) (OR:1.19, CI: [1.11, 1.28]), and East Asian American (EAA) (OR: 1.18, CI: [1.06, 1.31]) GIAs but not in African American (AA) GIA (OR: 1.04, CI: [0.93, 1.17]). Similarly, TUD-PGS offered strong risk stratification across PGS quantiles in EA and HL GIAs and inconsistently in EAA and AA GIAs. In a cross-ancestry phenome-wide association meta-analysis, TUD-PGS was associated with cardiometabolic, respiratory, and psychiatric phecodes (17 phecodes at P < 2.7E-05). In individuals with no history of smoking, the top TUD-PGS associations with obesity and alcohol-related disorders (P = 3.54E-07, 1.61E-06) persist. Mendelian Randomization (MR) analysis provides evidence of a causal association between adiposity measures and tobacco use. Inconsistent predictive performance of the TUD-PGS across GIAs motivates the inclusion of multiple ancestry populations at all levels of genetic research of tobacco use for equitable clinical translation of TUD-PGS. Phenome associations suggest that TUD-predisposed individuals may require comprehensive tobacco use prevention and management approaches to address underlying addictive tendencies.
Topics: Humans; Biological Specimen Banks; Los Angeles; Tobacco Use; Tobacco Use Disorder; Risk Factors; Obesity; Genome-Wide Association Study
PubMed: 38238290
DOI: 10.1038/s41398-024-02743-z -
Genome Medicine Jan 2024Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition...
BACKGROUND
Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and gain mechanistic insight. We expanded on these approaches by performing colocalization across GWAS traits while assessing the causality and directionality of genetic associations.
METHODS
We applied colocalization between T2D and 20 related metabolic traits, across 243 loci, to obtain inferences of shared casual variants. Network-based unsupervised hierarchical clustering was performed on variant-trait associations. Partitioned polygenic risk scores (PRSs) were generated for each cluster using T2D summary statistics and validated in 21,742 individuals with T2D from 3 cohorts. Inferences of directionality and causality were obtained by applying Mendelian randomization Steiger's Z-test and further validated in a pediatric cohort without diabetes (aged 9-12 years old, n = 3866).
RESULTS
We identified 146 T2D loci that colocalized with at least one metabolic trait locus. T2D variants within these loci were grouped into 5 clusters. The clusters corresponded to the following pathways: obesity, lipodystrophic insulin resistance, liver and lipid metabolism, hepatic glucose metabolism, and beta-cell dysfunction. We observed heterogeneity in associations between PRSs and metabolic measures across clusters. For instance, the lipodystrophic insulin resistance (Beta - 0.08 SD, 95% CI [- 0.10-0.07], p = 6.50 × 10) and beta-cell dysfunction (Beta - 0.10 SD, 95% CI [- 0.12, - 0.08], p = 1.46 × 10) PRSs were associated to lower BMI. Mendelian randomization Steiger analysis indicated that increased T2D risk in these pathways was causally associated to lower BMI. However, the obesity PRS was conversely associated with increased BMI (Beta 0.08 SD, 95% CI 0.06-0.10, p = 8.0 × 10). Analyses within a pediatric cohort supported this finding. Additionally, the lipodystrophic insulin resistance PRS was associated with a higher odds of chronic kidney disease (OR 1.29, 95% CI 1.02-1.62, p = 0.03).
CONCLUSIONS
We successfully partitioned T2D genetic variants into phenotypic pathways using a colocalization first approach. Partitioned PRSs were associated to unique metabolic and clinical outcomes indicating successful partitioning of disease heterogeneity. Our work expands on previous approaches by providing stronger inferences of shared causal variants, causality, and directionality of GWAS variant-trait associations.
Topics: Humans; Child; Diabetes Mellitus, Type 2; Genetic Risk Score; Insulin Resistance; Cluster Analysis; Obesity
PubMed: 38200577
DOI: 10.1186/s13073-023-01255-7 -
International Journal of Obesity (2005) May 2024Higher mean body mass index (BMI) among lower socioeconomic position (SEP) groups is well established in Western societies, but the influence of genetic factors on these...
BACKGROUND
Higher mean body mass index (BMI) among lower socioeconomic position (SEP) groups is well established in Western societies, but the influence of genetic factors on these differences is not well characterized.
METHODS
We analyzed these associations using Finnish health surveys conducted between 1992 and 2017 (N = 33 523; 53% women) with information on measured weight and height, polygenic risk scores of BMI (PGS-BMI) and linked data from administrative registers to measure educational attainment, occupation-based social class and personal income.
RESULTS
In linear regressions, largest adjusted BMI differences were found between basic and tertiary educated men (1.4 kg/m, 95% confidence interval [CI] 1.2; 1.6) and women (2.5 kg/m, 95% CI 2.3; 2.8), and inverse BMI gradients were also found for social class and income. These SEP differences arose partly because mean PGS-BMI was higher and partly because PGS-BMI predicted BMI more strongly in lower SEP groups. The inverse SEP gradients of BMI were steeper in women than in men, but sex differences were not found in the genetic contributions to these differences.
CONCLUSIONS
Better understanding of the interplay between genes and environment provides insight into the mechanisms explaining SEP differences in BMI.
Topics: Humans; Body Mass Index; Male; Female; Finland; Adult; Middle Aged; Socioeconomic Factors; Social Class; Obesity; Aged; Health Surveys
PubMed: 38200145
DOI: 10.1038/s41366-024-01459-w -
BioRxiv : the Preprint Server For... Dec 2023Skeletal muscle, the largest human organ by weight, is relevant to several polygenic metabolic traits and diseases including type 2 diabetes (T2D). Identifying genetic...
Skeletal muscle, the largest human organ by weight, is relevant to several polygenic metabolic traits and diseases including type 2 diabetes (T2D). Identifying genetic mechanisms underlying these traits requires pinpointing the relevant cell types, regulatory elements, target genes, and causal variants. Here, we used genetic multiplexing to generate population-scale single nucleus (sn) chromatin accessibility (snATAC-seq) and transcriptome (snRNA-seq) maps across 287 frozen human skeletal muscle biopsies representing 456,880 nuclei. We identified 13 cell types that collectively represented 983,155 ATAC summits. We integrated genetic variation to discover 6,866 expression quantitative trait loci (eQTL) and 100,928 chromatin accessibility QTL (caQTL) (5% FDR) across the five most abundant cell types, cataloging caQTL peaks that atlas-level snATAC maps often miss. We identified 1,973 eGenes colocalized with caQTL and used mediation analyses to construct causal directional maps for chromatin accessibility and gene expression. 3,378 genome-wide association study (GWAS) signals across 43 relevant traits colocalized with sn-e/caQTL, 52% in a cell-specific manner. 77% of GWAS signals colocalized with caQTL and not eQTL, highlighting the critical importance of population-scale chromatin profiling for GWAS functional studies. GWAS-caQTL colocalization showed distinct cell-specific regulatory paradigms. For example, a T2D GWAS signal colocalized with caQTL in muscle fibers and multiple chromatin loop models nominated , a glucose uptake gene. Sequence of the caQTL peak overlapping caSNP rs7163757 showed allelic regulatory activity differences in a human myocyte cell line massively parallel reporter assay. These results illuminate the genetic regulatory architecture of human skeletal muscle at high-resolution epigenomic, transcriptomic, and cell state scales and serve as a template for population-scale multi-omic mapping in complex tissues and traits.
PubMed: 38168419
DOI: 10.1101/2023.12.15.571696 -
Pacific Symposium on Biocomputing.... 2024Polygenic risk scores (PRS) have predominantly been derived from genome-wide association studies (GWAS) conducted in European ancestry (EUR) individuals. In this study,...
Polygenic risk scores (PRS) have predominantly been derived from genome-wide association studies (GWAS) conducted in European ancestry (EUR) individuals. In this study, we present an in-depth evaluation of PRS based on multi-ancestry GWAS for five cardiometabolic phenotypes in the Penn Medicine BioBank (PMBB) followed by a phenome-wide association study (PheWAS). We examine the PRS performance across all individuals and separately in African ancestry (AFR) and EUR ancestry groups. For AFR individuals, PRS derived using the multi-ancestry LD panel showed a higher effect size for four out of five PRSs (DBP, SBP, T2D, and BMI) than those derived from the AFR LD panel. In contrast, for EUR individuals, the multi-ancestry LD panel PRS demonstrated a higher effect size for two out of five PRSs (SBP and T2D) compared to the EUR LD panel. These findings underscore the potential benefits of utilizing a multi-ancestry LD panel for PRS derivation in diverse genetic backgrounds and demonstrate overall robustness in all individuals. Our results also revealed significant associations between PRS and various phenotypic categories. For instance, CAD PRS was linked with 18 phenotypes in AFR and 82 in EUR, while T2D PRS correlated with 84 phenotypes in AFR and 78 in EUR. Notably, associations like hyperlipidemia, renal failure, atrial fibrillation, coronary atherosclerosis, obesity, and hypertension were observed across different PRSs in both AFR and EUR groups, with varying effect sizes and significance levels. However, in AFR individuals, the strength and number of PRS associations with other phenotypes were generally reduced compared to EUR individuals. Our study underscores the need for future research to prioritize 1) conducting GWAS in diverse ancestry groups and 2) creating a cosmopolitan PRS methodology that is universally applicable across all genetic backgrounds. Such advances will foster a more equitable and personalized approach to precision medicine.
Topics: Humans; Genetic Risk Score; Genome-Wide Association Study; Genetic Predisposition to Disease; Precision Medicine; Multifactorial Inheritance; Computational Biology; Phenotype; Hypertension; Diabetes Mellitus, Type 2; Risk Factors
PubMed: 38160310
DOI: No ID Found -
PLoS Genetics Dec 2023To overcome the limitations associated with the collection and curation of COVID-19 outcome data in biobanks, this study proposes the use of polygenic risk scores (PRS)... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To overcome the limitations associated with the collection and curation of COVID-19 outcome data in biobanks, this study proposes the use of polygenic risk scores (PRS) as reliable proxies of COVID-19 severity across three large biobanks: the Michigan Genomics Initiative (MGI), UK Biobank (UKB), and NIH All of Us. The goal is to identify associations between pre-existing conditions and COVID-19 severity.
METHODS
Drawing on a sample of more than 500,000 individuals from the three biobanks, we conducted a phenome-wide association study (PheWAS) to identify associations between a PRS for COVID-19 severity, derived from a genome-wide association study on COVID-19 hospitalization, and clinical pre-existing, pre-pandemic phenotypes. We performed cohort-specific PRS PheWAS and a subsequent fixed-effects meta-analysis.
RESULTS
The current study uncovered 23 pre-existing conditions significantly associated with the COVID-19 severity PRS in cohort-specific analyses, of which 21 were observed in the UKB cohort and two in the MGI cohort. The meta-analysis yielded 27 significant phenotypes predominantly related to obesity, metabolic disorders, and cardiovascular conditions. After adjusting for body mass index, several clinical phenotypes, such as hypercholesterolemia and gastrointestinal disorders, remained associated with an increased risk of hospitalization following COVID-19 infection.
CONCLUSION
By employing PRS as a proxy for COVID-19 severity, we corroborated known risk factors and identified novel associations between pre-existing clinical phenotypes and COVID-19 severity. Our study highlights the potential value of using PRS when actual outcome data may be limited or inadequate for robust analyses.
Topics: Humans; Genome-Wide Association Study; Genetic Risk Score; COVID-19; Biological Specimen Banks; Preexisting Condition Coverage; Population Health; Risk Factors; Genetic Predisposition to Disease
PubMed: 38113267
DOI: 10.1371/journal.pgen.1010907 -
MedRxiv : the Preprint Server For... Dec 2023It is unknown whether the impact of high diet-quality and physical activity (PA) depends on the level of polygenic risk score (PRS) in different ancestries.
BACKGROUND
It is unknown whether the impact of high diet-quality and physical activity (PA) depends on the level of polygenic risk score (PRS) in different ancestries.
OBJECTIVE
Determine the associations and interactions between high-risk PRSs, dietary patterns, and high PA with atherosclerotic cardiovascular disease (ASCVD) in European Americans (EAs) and African Americans (AAs). Another aim determined the molecular pathways of PRS-mapped genes and their relationships with dietary intake.
METHODS
Cross-sectional analyses utilized de-identified data from 1987-2010 from 7-National Heart, Lung, and Blood Institute Candidate Gene Association Resource studies from the Database of Genotypes and Phenotypes studies for EAs (n=6,575) and AAs (n=1,606).
RESULTS
The high-risk PRS increased ASCVD risk by 59% (Risk Ratio=1.59;95% Confidence Interval:1.16-2.17) in the highest tertile for AAs and by 15% (RR=1.15;1.13-1.30) and 18% (RR=1.18;1.04-1.35) in the second and highest tertiles compared to the lowest tertile in EAs. Within the highest PRS tertiles, high PA-diet combinations (Dietary Approaches to Stop High Blood Pressure (DASH), or Mediterranean, or Southern) reduced ASCVD risks by 9% (RR=0.91;0.85-0.96) to 15% (RR=0.85;0.80-0.90) in EAs; and by 13% (RR=0.87;0.78-0.97) and 18% (RR=0.82;0.72-0.95) for the DASH and Mediterranean diets, respectively in AAs. Top molecular pathways included fructose metabolism and catabolism linked to obesity, insulin resistance, and type 2 diabetes in both ancestries. Additional molecular pathways for AAs were Vitamin D linked to depression and aging acceleration; and death signaling associated with cancer.
CONCLUSIONS
Effects of high diet-quality and high PA can counterbalance the influences of genetically high-risk PRSs on ASCVD risk, especially in AAs.
PubMed: 38106156
DOI: 10.1101/2023.12.05.23299548 -
Biological Psychiatry Global Open... Jan 2024Maternal inflammation can result from immune dysregulation and metabolic perturbations during pregnancy. Whether conditions associated with inflammation during pregnancy...
BACKGROUND
Maternal inflammation can result from immune dysregulation and metabolic perturbations during pregnancy. Whether conditions associated with inflammation during pregnancy increase the likelihood of autism spectrum disorder (ASD) or other neurodevelopmental disorders (DDs) is not well understood.
METHODS
We conducted a case-control study among children born in California from 2011 to 2016 to investigate maternal immune-mediated and cardiometabolic conditions during pregnancy and risk of ASD ( = 311) and DDs ( = 1291) compared with children from the general population ( = 967). Data on maternal conditions and covariates were retrieved from electronic health records. Maternal genetic data were used to assess a causal relationship.
RESULTS
Using multivariable logistic regression, we found that mothers with asthma were more likely to deliver infants later diagnosed with ASD (odds ratio [OR] = 1.62, 95% CI: 1.15-2.29) or DDs (OR = 1.30, 95% CI: 1.02-1.64). Maternal obesity was also associated with child ASD (OR = 1.51, 95% CI: 1.07-2.13). Mothers with both asthma and extreme obesity had the greatest odds of delivering an infant later diagnosed with ASD (OR = 16.9, 95% CI: 5.13-55.71). These increased ASD odds were observed among female children only. Polygenic risk scores for obesity, asthma, and their combination showed no association with ASD risk. Mendelian randomization did not support a causal relationship between maternal conditions and ASD.
CONCLUSIONS
Inflammatory conditions during pregnancy are associated with risk for neurodevelopmental disorders in children. These risks do not seem to be due to shared genetic risk; rather, inflammatory conditions may share nongenetic risk factors with neurodevelopmental disorders. Children whose mothers have both asthma and obesity during pregnancy may benefit from earlier screening and intervention.
PubMed: 38045769
DOI: 10.1016/j.bpsgos.2023.09.008 -
Diabetes, Metabolic Syndrome and... 2023Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases in Western countries, and its incidence is constantly increasing. Epidemiological studies have... (Review)
Review
Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases in Western countries, and its incidence is constantly increasing. Epidemiological studies have shown that in the next 20 years. The number of subjects affected by T2DM will double. In recent years, owing to the development and improvement in methods for studying the genome, several authors have evaluated the association between monogenic or polygenic genetic alterations and the development of metabolic diseases and complications. In addition, sedentary lifestyle and socio-economic and pandemic factors have a great impact on the habits of the population and have significantly contributed to the increase in the incidence of metabolic disorders, obesity, T2DM, metabolic syndrome, and liver steatosis. Moreover, patients with type 2 diabetes appear to respond to antihyperglycemic drugs. Only a minority of patients could be considered true non-responders. Thus, it appears clear that the main aim of precision medicine in T2DM is to identify patients who can benefit most from a specific drug class more than from the others. Precision medicine is a discipline that evaluates the applicability of genetic, lifestyle, and environmental factors to disease development. In particular, it evaluated whether these factors could affect the development of diseases and their complications, response to diet, lifestyle, and use of drugs. Thus, the objective is to find prevention models aimed at reducing the incidence of pathology and mortality and therapeutic personalized approaches, to obtain a greater probability of response and efficacy. This review aims to evaluate the applicability of precision medicine for T2DM, a healthcare burden in many countries.
PubMed: 38028995
DOI: 10.2147/DMSO.S390752