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Circulation Mar 2023Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies...
BACKGROUND
Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS.
METHODS
We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study.
RESULTS
We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS () and 6 were novel (). Two novel lead variants were associated in non-White individuals (<0.05): rs12740374 () in Black and Hispanic individuals and rs1522387 () in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [], rs12740374 []) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the locus. However, the locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis.
CONCLUSIONS
We performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.
Topics: Humans; Aged; Genome-Wide Association Study; Veterans; Genetic Predisposition to Disease; Aortic Valve Stenosis; Obesity; Transcription Factors; Lipoprotein(a); Lipoproteins, LDL; Cholesterol; Polymorphism, Single Nucleotide; Glycoproteins; Nuclear Proteins
PubMed: 36802703
DOI: 10.1161/CIRCULATIONAHA.122.061451 -
Nature Communications Jun 2022For any given level of overall adiposity, individuals vary considerably in fat distribution. The inherited basis of fat distribution in the general population is not...
For any given level of overall adiposity, individuals vary considerably in fat distribution. The inherited basis of fat distribution in the general population is not fully understood. Here, we study up to 38,965 UK Biobank participants with MRI-derived visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes. Because these fat depot volumes are highly correlated with BMI, we additionally study six local adiposity traits: VAT adjusted for BMI and height (VATadj), ASATadj, GFATadj, VAT/ASAT, VAT/GFAT, and ASAT/GFAT. We identify 250 independent common variants (39 newly-identified) associated with at least one trait, with many associations more pronounced in female participants. Rare variant association studies extend prior evidence for PDE3B as an important modulator of fat distribution. Local adiposity traits (1) highlight depot-specific genetic architecture and (2) enable construction of depot-specific polygenic scores that have divergent associations with type 2 diabetes and coronary artery disease. These results - using MRI-derived, BMI-independent measures of local adiposity - confirm fat distribution as a highly heritable trait with important implications for cardiometabolic health outcomes.
Topics: Adipose Tissue; Adiposity; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Intra-Abdominal Fat; Obesity; Subcutaneous Fat
PubMed: 35773277
DOI: 10.1038/s41467-022-30931-2 -
The Lancet. Global Health Mar 2023Large adulthood body size was associated with increased risk of osteoarthritis. We aimed to examine the association between body size trajectories from childhood to...
Associations of childhood-to-adulthood body size trajectories and genetic susceptibility with the risks of osteoarthritis: a population-based cohort study of UK Biobank data.
BACKGROUND
Large adulthood body size was associated with increased risk of osteoarthritis. We aimed to examine the association between body size trajectories from childhood to adulthood and potential interactions with genetic susceptibility on osteoarthritis risk.
METHODS
We included participants from the UK Biobank aged 38-73 years in 2006-10. Childhood body size information was collected by questionnaire. Adulthood BMI was assessed and transformed into three categories (<25 kg/m for normal, 25-29·9 kg/m for overweight, and >30 kg/m for obesity). A Cox proportional hazards regression model was applied to assess the association between body size trajectories and osteoarthritis incidence. Osteoarthritis-related polygenic risk score (PRS) was constructed to evaluate its interactions with body size trajectories on osteoarthritis risk.
FINDINGS
For the 466 292 participants included, we identified nine body size trajectories [thinner to normal (11·6%), overweight (17·2%), or obesity (26·9%); average to normal (11·8%), overweight (16·2%), or obesity (23·7%); and plumper to normal (12·3%), overweight (16·2%), or obesity (23·6%)]. Compared with individuals in the average-to-normal group, all other trajectory groups had higher risks of osteoarthritis, after adjustment for demographic, social-economic and lifestyle covariates (hazard ratios [HRs] 1·05-2·41; all p<0·01). Among them, thinner-to-obesity (HR 2·41; 95% CI 2·23-2·49) had the most prominent association with increased osteoarthritis risk. A high PRS was significantly associated with an increased risk of osteoarthritis (1·14; 1·11-1·16), whereas no interaction between childhood-to-adulthood body size trajectories and PRS on osteoarthritis risks was observed. The population attributable fraction suggested that body size towards normal in adulthood could eliminate osteoarthritis cases by 18·67% for thinner-to-overweight to 38·74% for plumper-to-obesity.
INTERPRETATION
Average-to-normal body size seems to be the healthiest childhood-to-adulthood trajectory for osteoarthritis risk, whereas a trajectory of increased body size from thinner to obesity has the highest risk for osteoarthritis. These associations are independent of osteoarthritis genetic susceptibility.
FUNDING
The National Natural Science Foundation of China (32000925) and Guangzhou Science and Technology Program (202002030481).
Topics: Humans; Child; Adolescent; Young Adult; Overweight; Biological Specimen Banks; Cohort Studies; Genetic Predisposition to Disease; Obesity; Body Size; Osteoarthritis; United Kingdom
PubMed: 36866477
DOI: 10.1016/S2214-109X(23)00087-6 -
ELife Jul 2023Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis... (Meta-Analysis)
Meta-Analysis
Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.
Topics: Animals; Mice; Osteogenesis; Genome-Wide Association Study; Diabetes Mellitus, Type 2; Spine; Ossification of Posterior Longitudinal Ligament
PubMed: 37461309
DOI: 10.7554/eLife.86514 -
Current Obesity Reports Dec 2023Enormous progress has been made in understanding the genetic architecture of obesity and the correlation of epigenetic marks with obesity and related traits. This review... (Review)
Review
PURPOSE OF REVIEW
Enormous progress has been made in understanding the genetic architecture of obesity and the correlation of epigenetic marks with obesity and related traits. This review highlights current research and its challenges in genetics and epigenetics of obesity.
RECENT FINDINGS
Recent progress in genetics of polygenic traits, particularly represented by genome-wide association studies, led to the discovery of hundreds of genetic variants associated with obesity, which allows constructing polygenic risk scores (PGS). In addition, epigenome-wide association studies helped identifying novel targets and methylation sites being important in the pathophysiology of obesity and which are essential for the generation of methylation risk scores (MRS). Despite their great potential for predicting the individual risk for obesity, the use of PGS and MRS remains challenging. Future research will likely discover more loci being involved in obesity, which will contribute to better understanding of the complex etiology of human obesity. The ultimate goal from a clinical perspective will be generating highly robust and accurate prediction scores allowing clinicians to predict obesity as well as individual responses to body weight loss-specific life-style interventions.
Topics: Humans; DNA Methylation; Genome-Wide Association Study; Epigenesis, Genetic; Obesity; Phenotype; Genetic Risk Score
PubMed: 37819541
DOI: 10.1007/s13679-023-00526-z -
BMC Medicine Jun 2022Body mass index (BMI) has been found to be associated with a decreased risk of non-small cell lung cancer (NSCLC); however, the effect of BMI trajectories and potential... (Clinical Trial)
Clinical Trial
BACKGROUND
Body mass index (BMI) has been found to be associated with a decreased risk of non-small cell lung cancer (NSCLC); however, the effect of BMI trajectories and potential interactions with genetic variants on NSCLC risk remain unknown.
METHODS
Cox proportional hazards regression model was applied to assess the association between BMI trajectory and NSCLC risk in a cohort of 138,110 participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. One-sample Mendelian randomization (MR) analysis was further used to access the causality between BMI trajectories and NSCLC risk. Additionally, polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between BMI trajectories and genetic variants in NSCLC risk.
RESULTS
Compared with individuals maintaining a stable normal BMI (n = 47,982, 34.74%), BMI trajectories from normal to overweight (n = 64,498, 46.70%), from normal to obese (n = 21,259, 15.39%), and from overweight to obese (n = 4,371, 3.16%) were associated with a decreased risk of NSCLC (hazard ratio [HR] for trend = 0.78, P < 2×10). An MR study using BMI trajectory associated with genetic variants revealed no significant association between BMI trajectories and NSCLC risk. Further analysis of PRS showed that a higher GWAS-identified PRS (PRS) was associated with an increased risk of NSCLC, while the interaction between BMI trajectories and PRS with the NSCLC risk was not significant (P= 0.863 and P= 0.704). In GWIA analysis, four independent susceptibility loci (P < 1×10) were found to be associated with BMI trajectories on NSCLC risk, including rs79297227 (12q14.1, located in SLC16A7, P = 1.01×10), rs2336652 (3p22.3, near CLASP2, P = 3.92×10), rs16018 (19p13.2, in CACNA1A, P = 3.92×10), and rs4726760 (7q34, near BRAF, P = 9.19×10). Functional annotation demonstrated that these loci may be involved in the development of NSCLC by regulating cell growth, differentiation, and inflammation.
CONCLUSIONS
Our study has shown an association between BMI trajectories, genetic factors, and NSCLC risk. Interestingly, four novel genetic loci were identified to interact with BMI trajectories on NSCLC risk, providing more support for the aetiology research of NSCLC.
TRIAL REGISTRATION
http://www.
CLINICALTRIALS
gov , NCT01696968 .
Topics: Body Mass Index; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Humans; Lung Neoplasms; Male; Obesity; Overweight; Risk Factors
PubMed: 35658861
DOI: 10.1186/s12916-022-02400-6 -
Journal of Hepatology Apr 2021Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty...
BACKGROUND & AIMS
Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification.
METHODS
We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5).
RESULTS
In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10) and without cirrhosis (p <0.05).
CONCLUSIONS
Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings.
LAY SUMMARY
By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.
Topics: Adiposity; Carcinoma, Hepatocellular; Cross-Sectional Studies; Europe; Female; Genetic Predisposition to Disease; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Mediation Analysis; Middle Aged; Multifactorial Inheritance; Non-alcoholic Fatty Liver Disease; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors
PubMed: 33248170
DOI: 10.1016/j.jhep.2020.11.024 -
Genes Feb 2024Sarcopenic obesity (SO) is a combination of obesity and sarcopenia, with diagnostic criteria defined as impaired skeletal muscle function and altered body composition... (Review)
Review
Sarcopenic obesity (SO) is a combination of obesity and sarcopenia, with diagnostic criteria defined as impaired skeletal muscle function and altered body composition (e.g., increased fat mass and reduced muscle mass). The mechanism of SO is not yet perfectly understood; however, the pathogenesis includes aging and its complications, chronic inflammation, insulin resistance (IR), and hormonal changes. Genetic background is apparent in the pathogenesis of isolated obesity, which is most often polygenic and is characterized by the additive effect of various genetic factors. The genetic etiology has not been strictly established in SO. Still, many data confirm the existence of pathogenic gene variants, e.g., Fat Mass and Obesity Associated Gene (), beta-2-adrenergic receptor () gene, melanocortin-4 receptor () and others with obesity. The literature on the role of these genes is scarce, and their role has not yet been thoroughly established. On the other hand, the involvement of systemic inflammation due to increased adipose tissue in SO plays a significant role in its pathophysiology through the synthesis of various cytokines such as monocyte chemoattractant protein-1 (MCP-1), IL-1Ra, IL-15, adiponectin or CRP. The lack of anti-inflammatory cytokine (e.g., IL-15) can increase SO risk, but further studies are needed to evaluate the exact mechanisms of implications of various cytokines in SO individuals. This manuscript analyses various immunogenetic and non-genetic factors and summarizes the recent findings on immunogenetics potentially impacting SO development.
Topics: Humans; Sarcopenia; Immunogenetics; Interleukin-15; Obesity; Inflammation; Alpha-Ketoglutarate-Dependent Dioxygenase FTO
PubMed: 38397196
DOI: 10.3390/genes15020206 -
JAMA Network Open Mar 2024Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is a commonly used estimate of obesity, which is a complex trait affected by...
IMPORTANCE
Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is a commonly used estimate of obesity, which is a complex trait affected by genetic and lifestyle factors. Marked weight gain and loss could be associated with adverse biological processes.
OBJECTIVE
To evaluate the association between BMI variability and incident cardiovascular disease (CVD) events in 2 distinct cohorts.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used data from the Million Veteran Program (MVP) between 2011 and 2018 and participants in the UK Biobank (UKB) enrolled between 2006 and 2010. Participants were followed up for a median of 3.8 (5th-95th percentile, 3.5) years. Participants with baseline CVD or cancer were excluded. Data were analyzed from September 2022 and September 2023.
EXPOSURE
BMI variability was calculated by the retrospective SD and coefficient of variation (CV) using multiple clinical BMI measurements up to the baseline.
MAIN OUTCOMES AND MEASURES
The main outcome was incident composite CVD events (incident nonfatal myocardial infarction, acute ischemic stroke, and cardiovascular death), assessed using Cox proportional hazards modeling after adjustment for CVD risk factors, including age, sex, mean BMI, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking status, diabetes status, and statin use. Secondary analysis assessed whether associations were dependent on the polygenic score of BMI.
RESULTS
Among 92 363 US veterans in the MVP cohort (81 675 [88%] male; mean [SD] age, 56.7 [14.1] years), there were 9695 Hispanic participants, 22 488 non-Hispanic Black participants, and 60 180 non-Hispanic White participants. A total of 4811 composite CVD events were observed from 2011 to 2018. The CV of BMI was associated with 16% higher risk for composite CVD across all groups (hazard ratio [HR], 1.16; 95% CI, 1.13-1.19). These associations were unchanged among subgroups and after adjustment for the polygenic score of BMI. The UKB cohort included 65 047 individuals (mean [SD] age, 57.30 (7.77) years; 38 065 [59%] female) and had 6934 composite CVD events. Each 1-SD increase in BMI variability in the UKB cohort was associated with 8% increased risk of cardiovascular death (HR, 1.08; 95% CI, 1.04-1.11).
CONCLUSIONS AND RELEVANCE
This cohort study found that among US veterans, higher BMI variability was a significant risk marker associated with adverse cardiovascular events independent of mean BMI across major racial and ethnic groups. Results were consistent in the UKB for the cardiovascular death end point. Further studies should investigate the phenotype of high BMI variability.
Topics: Female; Male; Humans; Middle Aged; Body Mass Index; Ischemic Stroke; Cohort Studies; Retrospective Studies; Myocardial Infarction; Cholesterol, HDL
PubMed: 38512255
DOI: 10.1001/jamanetworkopen.2024.3062