Multi-ancestry polygenic risk scores for venous thromboembolism.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx_combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx_combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE.

Evaluation of Plasma Biomarkers for Causal Association With Peripheral Artery Disease.

BACKGROUND: Hundreds of biomarkers for peripheral artery disease (PAD) have been reported in the literature; however, the observational nature of these studies limits causal inference due to the potential of reverse causality and residual confounding. We sought to evaluate the potential causal impact of putative PAD biomarkers identified in human observational studies through genetic causal inference methods. METHODS: Putative circulating PAD biomarkers were identified from human observational studies through a comprehensive literature search based on terms related to PAD using PubMed, Cochrane, and Embase. Genetic instruments were generated from publicly available genome-wide association studies of circulating biomarkers. Two-sample Mendelian randomization was used to test the association of genetically determined biomarker levels with PAD using summary statistics from a genome-wide association study of 31 307 individuals with and 211 753 individuals without PAD in the Veterans Affairs Million Veteran Program and replicated in data from FinnGen comprised of 11 924 individuals with and 288 638 individuals without PAD. RESULTS: We identified 204 unique circulating biomarkers for PAD from the observational literature, of which 173 were genetically instrumented using genome-wide association study results. After accounting for multiple testing (false discovery rate, <0.05), 10 of 173 (5.8%) biomarkers had significant associations with PAD. These 10 biomarkers represented categories including plasma lipoprotein regulation, lipid homeostasis, and protein-lipid complex remodeling. Observational literature highlighted different pathways including inflammatory response, negative regulation of multicellular organismal processes, and regulation of response to external stimuli. CONCLUSIONS: Integrating human observational studies and genetic causal inference highlights several key pathways in PAD pathophysiology. This work demonstrates that a substantial portion of biomarkers identified in observational studies are not well supported by human genetic evidence and emphasizes the importance of triangulating evidence to understand PAD pathophysiology. Although the identified biomarkers offer insights into atherosclerotic development in the lower limb, their specificity to PAD compared with more widespread atherosclerosis requires further study.

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program.

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 (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) 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 FTO locus. However, the FTO 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.

A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank.

'Genome-first' approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into 'gene burdens' for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these 'positive control' genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41 759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.

Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study.

Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of abdominal aortic aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in 10 cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects [Partners Biobank cohort 1 (PBIO)] as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In genome-wide association study (GWAS) on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, P-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (P-value = 8.19 × 10-4). In exome-array single-variant analysis (P-value threshold = 9 × 10-7), the lowest P-value was found for rs239259 located in SLC22A20 (beta = 0.007, P-value = 1.2 × 10-5). In the gene-based analysis (P-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (P-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, P-value = 0.02), triglycerides (beta = -0.16, P-value = 0.008) and height (beta = 0.03, P-value < 0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.

Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.

Gamification-augmented home-based exercise for peripheral artery disease: Rationale and design of the GAMEPAD Study.

BACKGROUND: Supervised exercise therapy improves walking performance, functional capacity, and quality of life in patients with peripheral artery disease (PAD). However, few patients with PAD are enrolled in supervised exercise programs, and there are a number of logistical and financial barriers to their participation. A home-based walking intervention is likely to be more accessible to patients with PAD, but no fully home-based walking program has demonstrated efficacy. Concepts from behavioral economics have been used to design scalable interventions that increase daily physical activity in patients with atherosclerotic vascular disease, but whether a similar program would be effective in patients with PAD is uncertain. STUDY DESIGN AND OBJECTIVES: GAMEPAD (NCT04536012) is a pragmatic, virtual, randomized controlled trial designed to evaluate the effectiveness of a gamification strategy informed by concepts from behavioral economics to increase daily physical activity in patients with PAD who are seen in cardiology and vascular surgery clinics affiliated with the University of Pennsylvania Health System. Patients are contacted by email or text message, and complete enrollment and informed consent on the Penn Way to Health online platform. A GAMEPAD substudy will evaluate the effectiveness of opt-in versus opt-out framing when approaching patients for study participation. Patients are then provided with a wearable fitness tracker, establish a baseline daily step count, set a goal to increase daily step count by 33%-50%, and are randomized 1:1 to the gamification or control arms. Interventions continue for 16 weeks, including a 4-week period during which goal step count is gradually increased in the gamification arm, with follow-up for an additional 8 weeks to evaluate the durability of behavior change. The trial has met its enrollment goal of 102 participants, with a primary endpoint of change from baseline in daily steps over the 16-week intervention period. Key secondary endpoints include change from baseline in daily steps over the 8-week postintervention follow-up period and changes in patient-reported measures of PAD symptoms and quality of life over the intervention and follow-up periods. CONCLUSIONS: GAMEPAD is a virtual, pragmatic randomized clinical trial of a novel, fully home-based walking intervention informed by concepts from behavioral economics to increase physical activity and PAD-specific quality of life in patients with PAD. Its results will have important implications for the application of behavioral economic concepts to scalable home-based strategies to promote physical activity in patients with PAD and other disease processes where physical activity is limited by exertional symptoms. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; NCT04536012.

Diastolic Blood Pressure Alleles Improve Congenital Heart Defect Repair Outcomes.

BACKGROUND: Congenital heart defects (CHDs) affect 40 000 US births per year, half of which require surgical intervention. Individual differences in surgical outcomes including mortality and complications are not well understood but may be due to genetic variability. We hypothesized that polygenic risk scores (PRSs) for blood pressure in adults are associated with treatments and postsurgical outcomes in children with CHD, as CHD survivors are at higher risk of negative cardiometabolic disease. METHODS: We used imputed genotype data from pediatric participants requiring surgery for CHD (median age at surgery, 201 days; nmax=2498). Base data for the systolic and diastolic blood pressure PRSs (nmax=760 226) came from published genome-wide association study. The blood pressure PRSs were tested for association with postsurgical outcomes. All effects presented are per SD increase in PRS and adjusted for age, sex, body mass index, surgical complexity score, and first 10 principal components of ancestry. RESULTS: A higher diastolic blood pressure PRS was associated with decreased in-hospital mortality risk (odds ratio, 0.57 [0.39-0.82]; P=0.0022). Additional analyses suggest an interaction between diastolic blood pressure PRS and vasopressor dose. Those with a diastolic blood pressure PRS 1 SD above the mean, receiving a vasopressor dose in the top tertile, were estimated to have 52% (32%-66%) lower risk of in-hospital mortality compared with those with a vasopressor dose in the bottom tertile. CONCLUSIONS: These results suggest a genetically determined postsurgical survival advantage for CHD patients with blood pressure increasing alleles. Further study may reveal novel mechanisms contributing to postoperative morbidity and mortality, and this approach may assist in early identification of children at risk for adverse postoperative outcomes.

Genome-Wide Association Study Identifies Genes for Hair Growth and Patterning are Associated With Pilonidal Disease.

BACKGROUND: Pilonidal sinus disease is a highly morbid condition characterized by the formation of chronic sinus tracts throughout the sacrococcygeal region. Despite its commonality and strong association with family history, there is no prior investigation of genetic risk factors for pilonidal sinus disease. OBJECTIVE: To identify genetic risk factors for pilonidal sinus disease. DESIGN: Genome-wide association study. SETTINGS: The United Kingdom Biobank, FinnGen Biobank, and PennMedicine Biobank. PATIENTS: There were 772,072 participants. MAIN OUTCOME MEASURE: Genome-wide significant variants (p < 5x10 -8) were mapped to genes using physical distance and gene expression in skin. Genetic correlation between pilonidal sinus disease and morphometric, androgen-driven, and hair phenotypes was estimated with LD score regression. Finally, a genome-first approach to rare, predicted deleterious variants in hair shaft genes TCHH, PADI3, and TGM3 was conducted for association with pilonidal sinus disease via PennMedicine Biobank. RESULTS: Genome-wide association study comprised of 2,835 individuals with pilonidal sinus disease identified 5 genome-wide significant loci, prioritizing HDAC9, TBX15, WARS2, RP11-293M10.1, PRKAR1B, TWIST1, GPATCH2L, NEK9, and EIF2B2, as putative causal genes; several of these genes have known roles in balding and hair patterning. There was significant correlation between the genetic background of pilonidal sinus disease and that of the androgen-driven hair traits male pattern baldness and young age at first facial hair. In a candidate analysis of genes associated with syndromic hair disorders, rare coding variants in TCHH, a monogenic cause of uncombable hair syndrome, were associated with increased prevalence of pilonidal sinus disease (OR 4.81 [5% CI, 2.06-11.2]). LIMITATIONS: This study is limited to European ancestry. However, because there is a higher incidence of pilonidal sinus disease in men of European ancestry, this analysis is focused on the at-risk population. CONCLUSION: Genetic analysis of pilonidal sinus disease identified shared genetic architecture with hair biology and androgen-driven traits. As the first study investigating the genetic basis of pilonidal sinus disease, this provides biological insight into the long-appreciated connection between the disease state, male gender, and hair. See Video abstract.

Relationship Between Ascending Thoracic Aortic Diameter and Blood Pressure: A Mendelian Randomization Study.

BACKGROUND: Observational studies identified elevated blood pressure (BP) as a strong risk factor for thoracic aortic dilation, and BP reduction is the primary medical intervention recommended to prevent progression of aortic aneurysms. However, although BP may impact aortic dilation, aortic size may also impact BP. The causal relationship between BP and thoracic aortic size has not been reliably established. METHODS: Genome-wide association studies summary statistics were obtained for BP and ascending thoracic aortic diameter (AscAoD). Causal effects of BP on AscAoD were estimated using 2-sample Mendelian randomization using a range of pleiotropy-robust methods. RESULTS: Genetically predicted increased systolic BP, diastolic BP, and mean arterial pressure all significantly associate with higher AscAoD (systolic BP: ß estimate, 0.0041 mm/mm Hg [95% CI, 0.0008-0.0074]; P=0.02, diastolic BP: ß estimate, 0.0272 mm/mm Hg [95% CI, 0.0224-0.0320]; P<0.001, and mean arterial pressure: ß estimate, 0.0168 mm/mm Hg [95% CI, 0.0130-0.0206]; P<0.001). Genetically predicted pulse pressure, meanwhile, had an inverse association with AscAoD (ß estimate, -0.0155 mm/mm Hg [95% CI, -0.0213 to -0.0096]; P<0.001). Multivariable Mendelian randomization analyses showed that genetically predicted increased mean arterial pressure and reduced pulse pressure were independently associated with AscAoD. Bidirectional Mendelian randomization demonstrated that genetically predicted AscAoD was inversely associated with pulse pressure (ß estimate, -2.0721 mm Hg/mm [95% CI, -3.1137 to -1.0306]; P<0.001) and systolic BP (ß estimate, -1.2878 mm Hg/mm [95% CI, -2.3533 to -0.2224]; P=0.02), while directly associated with diastolic BP (0.8203 mm Hg/mm [95% CI, 0.2735-1.3672]; P=0.004). CONCLUSIONS: BP likely contributes causally to ascending thoracic aortic dilation. Increased AscAoD likely contributes to lower systolic BP and pulse pressure, but not diastolic BP, consistent with the hemodynamic consequences of a reduced aortic diameter.

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Cardiovascular disease is the leading contributor to years lost due to disability or premature death among adults. Current efforts focus on risk prediction and risk factor mitigation' which have been recognized for the past half-century. However, despite advances, risk prediction remains imprecise with persistently high rates of incident cardiovascular disease. Genetic characterization has been proposed as an approach to enable earlier and potentially tailored prevention. Rare mendelian pathogenic variants predisposing to cardiometabolic conditions have long been known to contribute to disease risk in some families. However, twin and familial aggregation studies imply that diverse cardiovascular conditions are heritable in the general population. Significant technological and methodological advances since the Human Genome Project are facilitating population-based comprehensive genetic profiling at decreasing costs. Genome-wide association studies from such endeavors continue to elucidate causal mechanisms for cardiovascular diseases. Systematic cataloging for cardiovascular risk alleles also enabled the development of polygenic risk scores. Genetic profiling is becoming widespread in large-scale research, including in health care-associated biobanks, randomized controlled trials, and direct-to-consumer profiling in tens of millions of people. Thus, individuals and their physicians are increasingly presented with polygenic risk scores for cardiovascular conditions in clinical encounters. In this scientific statement, we review the contemporary science, clinical considerations, and future challenges for polygenic risk scores for cardiovascular diseases. We selected 5 cardiometabolic diseases (coronary artery disease, hypercholesterolemia, type 2 diabetes, atrial fibrillation, and venous thromboembolic disease) and response to drug therapy and offer provisional guidance to health care professionals, researchers, policymakers, and patients.

Plasma protein and venous thromboembolism: prospective cohort and mendelian randomisation analyses.

We conducted cohort and Mendelian randomisation (MR) analyses to examine the associations of circulating proteins with risk of venous thromboembolism (VTE) to provide evidence basis for disease prevention and drug development. Cohort analysis was performed in 11 803 participants without baseline VTE. Cox regression was used to estimate the associations between 257 proteins and VTE risk. A machine-learning model was constructed to compare the importance of identified proteins and traditional risk factors. Genetic association data on VTE were obtained from a genome-wide meta-analysis (26 066 cases and 624 053 controls) and FinnGen (14 454 cases and 294 700 controls). The cohort analysis, including 353 incident VTE cases diagnosed during a 6.6-year follow-up, identified 21 proteins associated with VTE risk after false discovery rate correction. The machine-learning model indicated that body mass index and von Willebrand factor (vWF) made the same as well as most of the contributions to the overall model prediction. MR analysis found that genetically predicted levels of vWF, SERPINE1 (plasminogen activator inhibitor 1, known as PAI-1), EPHB4 (ephrin type-B receptor 4), TYRO3 (tyrosine-protein kinase receptor TYRO3), TNFRSF11A (tumour necrosis factor receptor superfamily member 11A), and BOC (brother of CDO) were causally associated with VTE risk.

Genetics of atrial fibrillation.

PURPOSE OF REVIEW: Atrial fibrillation is the most common cardiac arrhythmia worldwide. There is considerable interest in better understanding the molecular genetics and biology of atrial fibrillation to inform the development of new therapies and improve clinical management. This review summarizes recent advances in our understanding of the genetic basis of atrial fibrillation and new efforts to utilize genetics to inform clinical management. RECENT FINDINGS: Genome-wide association studies in diverse populations have increased the number of genetic loci associated with atrial fibrillation and its specific subtypes. Large-scale biobanks with deep phenotyping have provided invaluable data to study the impact of both common and rare variants on atrial fibrillation, susceptibility, and prognosis. Polygenic risk scores help improve individual atrial fibrillation risk stratification and prognostication. SUMMARY: Our understanding of atrial fibrillation genetics is rapidly improving with larger and more diverse genome-wide association studies. Translating genetic discoveries into molecular pathways and new therapeutic targets remains a bottleneck in the development of new therapies for atrial fibrillation. Genetic risk scores have shown early promise in improving atrial fibrillation risk stratification; however, their broader utility for the general population remains unclear.

Genetic Determinants of Peripheral Artery Disease.

Peripheral artery disease-atherosclerosis of the abdominal aorta and lower extremity vascular bed-is a complex disease with both environmental and genetic determinants. Unmitigated disease is associated with major functional decline and can lead to chronic limb-threatening ischemia, amputation, and increased mortality. Over the last 10 years, major advances have been made in identifying the genetic basis of this common, complex disease. In this review, we provide an overview of the primary types of genetic analyses performed for peripheral artery disease, including heritability and linkage studies, and more recently biobank-based genome-wide association studies. Looking forward, we highlight areas of future study including efforts to identify causal peripheral artery disease genes, rare variant and structural variant analyses using whole-exome and whole-genome sequencing data, and the need to include individuals of diverse genetic ancestries.

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.

Separating the direct effects of traits on atherosclerotic cardiovascular disease from those mediated by type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes and atherosclerotic CVD share many risk factors. This study aimed to systematically assess a broad range of continuous traits to separate their direct effects on coronary and peripheral artery disease from those mediated by type 2 diabetes. METHODS: Our main analysis was a two-step Mendelian randomisation for mediation to quantify the extent to which the associations observed between continuous traits and liability to atherosclerotic CVD were mediated by liability to type 2 diabetes. To support this analysis, we performed several univariate Mendelian randomisation analyses to examine the associations between our continuous traits, liability to type 2 diabetes and liability to atherosclerotic CVD. RESULTS: Eight traits were eligible for the two-step Mendelian randomisation with liability to coronary artery disease as the outcome and we found similar direct and total effects in most cases. Exceptions included fasting insulin and hip circumference where the proportion mediated by liability to type 2 diabetes was estimated as 56% and 52%, respectively. Six traits were eligible for the analysis with liability to peripheral artery disease as the outcome. Again, we found limited evidence to support mediation by liability to type 2 diabetes for all traits apart from fasting insulin (proportion mediated: 70%). CONCLUSIONS/INTERPRETATION: Most traits were found to affect liability to atherosclerotic CVD independently of their relationship with liability to type 2 diabetes. These traits are therefore important for understanding atherosclerotic CVD risk regardless of an individual's liability to type 2 diabetes.

Prioritizing the Role of Major Lipoproteins and Subfractions as Risk Factors for Peripheral Artery Disease.

BACKGROUND: Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk. METHODS: Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies. RESULTS: ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86; P=0.003) and CAD (marginal inclusion probability, 0.92; P=0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB [95% CI, 0.84-0.91]; P=9×10-10) and CAD (odds ratio,0.66 [95% CI, 0.63-0.69]; P=4×10-73), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29-4.60]; P<1×10-6). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91; P=2.3×10-4), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95; P=0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 [95% CI, 1.03-1.04]; P=1.0×10-33). CONCLUSIONS: ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.

Genetic determinants of increased body mass index mediate the effect of smoking on increased risk for type 2 diabetes but not coronary artery disease.

Clinical observations have linked tobacco smoking with increased type 2 diabetes risk. Mendelian randomization analysis has recently suggested smoking may be a causal risk factor for type 2 diabetes. However, this association could be mediated by additional risk factors correlated with smoking behavior, which have not been investigated. We hypothesized that body mass index (BMI) could help to explain the association between smoking and diabetes risk. First, we confirmed that genetic determinants of smoking initiation increased risk for type 2 diabetes (OR 1.21, 95% CI: 1.15-1.27, P = 1 × 10-12) and coronary artery disease (CAD; OR 1.21, 95% CI: 1.16-1.26, P = 2 × 10-20). Additionally, 2-fold increased smoking risk was positively associated with increased BMI (~0.8 kg/m2, 95% CI: 0.54-0.98 kg/m2, P = 1.8 × 10-11). Multivariable Mendelian randomization analyses showed that BMI accounted for nearly all the risk smoking exerted on type 2 diabetes (OR 1.06, 95% CI: 1.01-1.11, P = 0.03). In contrast, the independent effect of smoking on increased CAD risk persisted (OR 1.12, 95% CI: 1.08-1.17, P = 3 × 10-8). Causal mediation analyses agreed with these estimates. Furthermore, analysis using individual-level data from the Million Veteran Program independently replicated the association of smoking behavior with CAD (OR 1.24, 95% CI: 1.12-1.37, P = 2 × 10-5), but not type 2 diabetes (OR 0.98, 95% CI: 0.89-1.08, P = 0.69), after controlling for BMI. Our findings support a model whereby genetic determinants of smoking increase type 2 diabetes risk indirectly through their relationship with obesity. Smokers should be advised to stop smoking to limit type 2 diabetes and CAD risk. Therapeutic efforts should consider pathophysiology relating smoking and obesity.