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.

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Whole-exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors.

Plasma levels of fibrinogen, coagulation factors VII and VIII and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole-exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the National Heart, Lung and Blood Institute's Exome Sequencing Project. Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in fibrinogen gamma chain (FGG) (with fibrinogen, P = 9.1 × 10-13), coagulation factor VII (F7) (with factor VII, P = 1.3 × 10-72; seven novel variants) and VWF (with factor VIII and vWF; P = 3.2 × 10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; P = 4.2 × 10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to AAs (rs3211938) in CD36 molecule (CD36). This variant has previously been linked to dyslipidemia but not with the levels of a hemostatic factor. These efforts represent the largest integration of whole-exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.

BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.

Chronic respiratory symptoms following deployment-related occupational and environmental exposures among US veterans.

OBJECTIVES: Characterise inhalational exposures during deployment to Afghanistan and Southwest Asia and associations with postdeployment respiratory symptoms. METHODS: Participants (n=1960) in this cross-sectional study of US Veterans (Veterans Affairs Cooperative Study 'Service and Health Among Deployed Veterans') completed an interviewer-administered questionnaire regarding 32 deployment exposures, grouped a priori into six categories: burn pit smoke; other combustion sources; engine exhaust; mechanical and desert dusts; toxicants; and military job-related vapours gas, dusts or fumes (VGDF). Responses were scored ordinally (0, 1, 2) according to exposure frequency. Factor analysis supported item reduction and category consolidation yielding 28 exposure items in 5 categories. Generalised linear models with a logit link tested associations with symptoms (by respiratory health questionnaire) adjusting for other covariates. OR were scaled per 20-point score increment (normalised maximum=100). RESULTS: The cohort mean age was 40.7 years with a median deployment duration of 11.7 months. Heavy exposures to multiple inhalational exposures were commonly reported, including burn pit smoke (72.7%) and VGDF (72.0%). The prevalence of dyspnoea, chronic bronchitis and wheeze in the past 12 months was 7.3%, 8.2% and 15.6%, respectively. Burn pit smoke exposure was associated with dyspnoea (OR 1.22; 95% CI 1.06 to 1.47) and chronic bronchitis (OR 1.22; 95% CI 1.13 to 1.44). Exposure to VGDF was associated with dyspnoea (OR 1.29; 95% CI 1.14 to 1.58) and wheeze (OR 1.18; 95% CI 1.02 to 1.35). CONCLUSION: Exposures to burn pit smoke and military occupational VGDF during deployment were associated with an increased odds of chronic respiratory symptoms among US Veterans.

Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation.

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, âˆ¼1.2), the A1 and B haplotypes are associated with an âˆ¼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, âˆ¼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.

Epidemiology and Genetics of Venous Thromboembolism and Chronic Venous Disease.

Venous disease is a term that broadly covers both venous thromboembolic disease and chronic venous disease. The basic pathophysiology of venous thromboembolism and chronic venous disease differ as venous thromboembolism results from an imbalance of hemostasis and thrombosis while chronic venous disease occurs in the setting of tissue damage because of prolonged venous hypertension. Both diseases are common and account for significant mortality and morbidity, respectively, and collectively make up a large health care burden. Despite both diseases having well-characterized environmental components, it has been known for decades that family history is an important risk factor, implicating a genetic element to a patient's risk. Our understanding of the pathogenesis of these diseases has greatly benefited from an expansion of population genetic studies from pioneering familial studies to large genome-wide association studies; we now have multiple risk loci for each venous disease. In this review, we will highlight the current state of knowledge on the epidemiology and genetics of venous thromboembolism and chronic venous disease and directions for future research.

Association between PTSD and Impedance Cardiogram-based contractility metrics during trauma recall: A controlled twin study.

Post-traumatic stress disorder (PTSD) is an independent risk factor for incident heart failure, but the underlying cardiac mechanisms remained elusive. Impedance cardiography (ICG), especially when measured during stress, can help understand the underlying psychophysiological pathways linking PTSD with heart failure. We investigated the association between PTSD and ICG-based contractility metrics (pre-ejection period (PEP) and Heather index (HI)) using a controlled twin study design with a laboratory-based traumatic reminder stressor. PTSD status was assessed using structured clinical interviews. We acquired synchronized electrocardiograms and ICG data while playing personalized-trauma scripts. Using linear mixed-effects models, we examined twins as individuals and within PTSD-discordant pairs. We studied 137 male veterans (48 pairs, 41 unpaired singles) from Vietnam War Era with a mean (standard deviation) age of 68.5(2.5) years. HI during trauma stress was lower in the PTSD vs. non-PTSD individuals (7.2 vs. 9.3 [ohm/s2 ], p = .003). PEP reactivity (trauma minus neutral) was also more negative in PTSD vs. non-PTSD individuals (-7.4 vs. -2.0 [ms], p = .009). The HI and PEP associations with PTSD persisted for adjusted models during trauma and reactivity, respectively. For within-pair analysis of eight PTSD-discordant twin pairs (out of 48 pairs), PTSD was associated with lower HI in neutral, trauma, and reactivity, whereas no association was found between PTSD and PEP. PTSD was associated with reduced HI and PEP, especially with trauma recall stress. This combination of increased sympathetic activation and decreased cardiac contractility combined may be concerning for increased heart failure risk after recurrent trauma re-experiencing in PTSD.

Efficient Variant Set Mixed Model Association Tests for Continuous and Binary Traits in Large-Scale Whole-Genome Sequencing Studies.

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.

A Mendelian randomization of γ' and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke.

Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ') fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ' fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ' fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ' fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ' fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ' fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ' fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.

Mendelian Randomization Analysis of Hemostatic Factors and Their Contribution to Peripheral Artery Disease-Brief Report.

BACKGROUND AND OBJECTIVE: Peripheral artery disease (PAD) is the third most common form of atherosclerotic vascular disease and is characterized by significant functional disability and increased cardiovascular mortality. Recent genetic data support a role for a procoagulation protein variant, the factor V Leiden mutation, in PAD. The role of other hemostatic factors in PAD remains unknown. We evaluated the role of hemostatic factors in PAD using Mendelian randomization. Approach and Results: Two-sample Mendelian randomization to evaluate the roles of FVII (factor VII), FVIII (factor VIII), FXI (factor XI), VWF (von Willebrand factor), and fibrinogen in PAD was performed using summary statistics from GWAS for hemostatic factors performed within the Cohorts for Heart and Aging Research in the Genome Epidemiology Consortium and from GWAS performed for PAD within the Million Veteran Program. Genetically determined FVIII and VWF, but not FVII, FXI, or fibrinogen, were associated with PAD in Mendelian randomization experiments (FVIII: odds ratio, 1.41 [95% CI, 1.23-1.62], P=6.0×10-7, VWF: odds ratio, 1.28 [95% CI, 1.07-1.52], P=0.0073). In single variant sensitivity analysis, the ABO locus was the strongest genetic instrument for both FVIII and VWF. CONCLUSIONS: Our results suggest a role for hemostasis, and by extension, thrombosis in PAD. Further study is warranted to determine whether VWF and FVIII independently affect the biology of PAD.

Association between depression and epigenetic age acceleration: A co-twin control study.

INTRODUCTION: Prior studies have shown inconsistent findings of an association between depression and epigenetic aging. DNA methylation (DNAm) age acceleration can measure biological aging. We adopted a robust co-twin control study design to examine whether depression is associated with DNAm age acceleration after accounting for the potential confounding influences of genetics and family environment. METHODS: We analyzed data on a sub-cohort of the Vietnam Era Twin Registry. A total of 291 twins participated at baseline and 177 at follow-up visit after a mean of 11.7 years, with 111 participants having DNA samples for both time points. Depression was measured using the Beck Depression Inventory II (BDI-II). Six measures of DNAm age acceleration were computed at each time point, including Horvath's DNAm age acceleration (HorvathAA), intrinsic epigenetic age acceleration (IEAA), Hannum's DNAm age acceleration (HannumAA), extrinsic epigenetic age acceleration (EEAA), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA). Mixed-effects modeling was used to assess the within-pair association between depression and DNAm age acceleration. RESULTS: At baseline, a 10-unit higher BDI-II total score was associated with HannumAA (0.73 years, 95% confidence interval [CI] 0.13-1.33, p = .019) and EEAA (0.94 years, 95% CI 0.22-1.66, p = .012). At follow-up, 10-unit higher BDI-II score was associated with PhenoAA (1.32 years, 95% CI 0.18-2.47, p = .027). CONCLUSION: We identified that depression is associated with higher levels of DNAm age acceleration. Further investigation is warranted to better understand the underlying mechanisms for the potential causal relationship between depression and accelerated aging.

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Early Convalescent Plasma Therapy and Mortality Among US Veterans Hospitalized With Nonsevere COVID-19: An Observational Analysis Emulating a Target Trial.

BACKGROUND: Early convalescent plasma transfusion may reduce mortality in patients with nonsevere coronavirus disease 2019 (COVID-19). METHODS: This study emulates a (hypothetical) target trial using observational data from a cohort of US veterans admitted to a Department of Veterans Affairs (VA) facility between 1 May and 17 November 2020 with nonsevere COVID-19. The intervention was convalescent plasma initiated within 2 days of eligibility. Thirty-day mortality was compared using cumulative incidence curves, risk differences, and hazard ratios estimated from pooled logistic models with inverse probability weighting to adjust for confounding. RESULTS: Of 11 269 eligible person-trials contributed by 4755 patients, 402 trials were assigned to the convalescent plasma group. Forty and 671 deaths occurred within the plasma and nonplasma groups, respectively. The estimated 30-day mortality risk was 6.5% (95% confidence interval [CI], 4.0%-9.7%) in the plasma group and 6.2% (95% CI, 5.6%-7.0%) in the nonplasma group. The associated risk difference was 0.30% (95% CI, -2.30% to 3.60%) and the hazard ratio was 1.04 (95% CI, .64-1.62). CONCLUSIONS: Our target trial emulation estimated no meaningful differences in 30-day mortality between nonsevere COVID-19 patients treated and untreated with convalescent plasma. Clinical Trials Registration. NCT04545047.

A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

Lifestyle Moderates Genetic Risk of Venous Thromboembolism: The ARIC Study.

OBJECTIVE: Venous thromboembolism (VTE) is a common disease that has a genetic basis. Lifestyle factors contribute to risk, but it is unknown whether healthy lifestyle can mitigate the genetic risk. We studied whether greater adherence to the American Heart Association's cardiovascular health metric, Life's Simple 7 (LS7), is associated with lower incidence of VTE in individuals across categories of a genetic risk score (GRS) for VTE. Approach AND RESULTS: We followed 9026 White participants from the ARIC (Atherosclerosis Risk in Communities) Study, a prospective cohort enrolled in 1987 to 1989 until 2015. We tested the joint associations with VTE of a validated VTE GRS comprising 5 well-known gene variants and baseline LS7 categories. There were 466 incident VTE events over 22.8 years. Participants with an optimal LS7 score had a lower incidence of VTE (3.9%) than those with inadequate LS7 (5.7%). Compared with the high GRS and inadequate LS7 group (hazard ratio=1), those with high GRS and optimal LS7 indeed had a reduced hazard ratio of VTE: 0.65 (95% CI, 0.48-0.89). The group with low GRS and optimal LS7 had the lowest hazard ratio of VTE (0.39 [95% CI, 0.25-0.61]). Of the LS7 components, in all GRS groups, the factor most strongly protective for VTE was normal weight. CONCLUSIONS: Among people at low or high genetic risk for VTE, healthier lifestyle factors, particularly normal weight, were associated with a lower incidence of VTE. Further studies should determine the impact of lifestyle changes among patients at high genetic risk of VTE, such as in thrombophilic families.

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

A large-scale exome array analysis of venous thromboembolism.

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.