Cardiovascular Genomics and Bioinformatics projects

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

There are several components of the research program. Component 1: Platelet Biology, Reactivity and Genomics. Utilizing one of the largest human samples (FHS: Framingham Heart Study) with platelet reactivity we have conducted deeper genetic scans for contributing genes. These scans use new genetic maps with deeper coverage of rare variation. DNA genotyping of an additional diverse population sample, the FHS OMNI cohort, was supported allowing additional validation samples and gene coverage for platelet reactivity traits. Further support was provided for genotyping of the U.K.-based Caerphilly Study in Men cohort, a rich study repository of hemostatic factor and platelet reactivity trait data. New genetic studies in 2018-19 led by the lab expanded the SNP platforms and imputation used to study platelet traits to include TOPMed WGS studies (presented at ASHG 2018; ISTH 2019; published in 2021 in Nature Communications). GWAS studies in the Caerphilly study have been completed leading to a major new gene discovery with new functional experiments leading to a new platelet gene mechanism through the GRK5 gene with this published in 2020 in AJHG. This gene has been casually linked to both venous and arterial cardiovascular disease now and could represent a novel drug target. Further biochemical work on GRK5 and Grk5 platelet-specific knockout mice (collaboration with Craig Morrel/Rochester). The latter confirmed the role of Grk5 in mouse thrombin signaling, and a platelet-specific causal role in thrombosis and pulmonary embolism (published in 2024 in RPTH). The analysis of large populations for the genetics of PLT (platelet count) and MPV (mean platelet volume) has resulted in scores of novel loci, including in non-European populations (2 manuscripts accepted including 1 led by the Johnson Lab to the top journal Cell published Sep 2020). In 2021, we published the largest WGS analysis to date of PLT and MPV (Little et al., HMG). We have continued to support the analysis and inclusion of FHS venous thromboembolism (VTE cases) and are working to update VTE event surveillance in FHS. We are co-leading the largest VTE case/control genetic analysis to date combining data from the INVENT Consortium, the Million Veteran's Project, the GBMI Consortium and others. This was presented in an invited oral presentation at ISTH2021 by our post-doc Dr. Florian Thibord, and published in a leading cardiovascular research journal Circulation in 2022. We also contributed FHS data and led the exome-chip gene mapping study of hemostatic factors PAI1, tPA and D-dimer that led to a new discovery of FGL1 (fibrinogen-like 1) (Thibord et al, 2021 JTH). In order to assess the contribution of platelet and other hemostasis genetics to the most-common bleeding condition (heavy menstrual bleeding), we led the largest genetic study to date on HMB (84,633 cases, 598195 controls). This study discovered 33 novel genetic loci for HMB and established the first Polygenic Risk Score (PRS) for HMB (Thibord et al., 2025 Blood). In 2024-2025, this work continued in new projects that aimed to expand the sample size of studies on these and related traits (i.e., VTE, cell counts, platelet reactivity), with new manuscript submissions expected in 2025-2026. A major initiative in the lab is large-scale platelet data collection in the FHS Gen3/Omni2 Exam 3 which has now been extended to the Gen2/Omni1 cohorts. Deep data collection was started in April 2016 and data on >3,200 samples were completed in April 2019. New data collection in Gen2/Omni2 commenced in the last period in Oct 2019 and is ongoing, encountering significant delays due to the COVID-19 pandemic. These data are being carefully cleaned and integrated with other FHS datasets to fuel new platelet genetic and epidemiology projects in the coming years, with preliminary results already being presented at scientific meetings. New platelet function was initiated, led by the Lab, in 2018 in the Boston Puerto Rican Health Study in an effort to expand diverse genetic and epidemiological studies of platelet function with data collection ending in 2020 and data cleaning completed in 2021. This data and FHS data are included in a submitted manuscript documenting strong associations of anti-depressant use with suppressing platelet function (Grech et al., 2021 CPT). Additional efforts uncovered links between alcohol and platelet reactivity (Pashek et al., 2023 Int J Epi), lipids and platelet reactivity (Nkambule et al., 2023 Thromb Res), and subclinical atherosclersois/calcification and vessel parameters (Cunha et al., 2023 Platelets). Recently, we published one of the most comprehensive studies examining medication, environmental and technical factors influencing platelet assays (Chan et al., 2024 RPTH), as well as showing that physically fit individuals have lower platelet reactivity even after accounting for other factors (Grech et al., 2024). In the 2020 year we proposed a major new platelet function study in the Jackson Heart Study which will be the largest data collection on platelet function in African ancestry individuals. Due to COVID-19 the start of that data collection has been delayed significantly and actively commenced in May 2023 and initial data collection did not complete until mid-2025. Data cleaning and measurements on collected frozen samples will proceed in 2025-2026. Component 2: Tissue-specific Gene Expression. A major cell- and tissue-specific database of genetic factors on gene expression (eQTLs) was maintained. This catalog was used to add information on genes to many disease and risk factor studies, primarily in the cardiovascular and metabolic disease domains. In 2019 we have utilized a publicly available platelet SNP and microarray dataset to re-impute genetic markers and expand knowledge of platelet eQTLs, as well how they are enriched for megakaryocyte epigenetic signatures. These data have been utilized in our research efforts (e.g., 2020 paper in AJHG). We also contributed our analysis resources to the largest platelet eQTL study to date (Kammers et al., 2020 Blood). We are in the early stages of a large-scale effort at platelet RNA-sequencing in hundreds of individuals from the FHS study. In 2023 we wrote a cutting edge review paper on Platelet RNA-seq (Thibord & Johnson, 2023 Thromb Res), in anticipation of our continued emerging research in this area. Dr. Thibord presented 2 related oral presentations at the ISTH 2023 meeting in Montreal, as well as Dr. Johnson presenting 1 invited oral presentation there on Platelet genomics. Dr. Thibord presented analysis on medication associations with the platelet transcriptome at the ISTH 2024 meeting. Additional sequencing efforts are underway in the next Fiscal years to diversify samples with platelet RNA-seq via the TOPMed program. It is expected that the first platelet RNA-seq papers will be published in 2025-2026. Component 3: Longitudinal study of Platelet biology. A new study PVLMO (Platelet Volunteers, Longitudinal and Multi-Omic) is being launched in 2025-2026 to recruit health volunteers who will be followed over a period of time with multiple blood draws. The PVLMO study will enable an in depth examination of how platelet measurements and blood biomarkers vary and change over time, what environmental and health factors influence these, and how all of them interact with multi-OMIC biomarkers. This study also allows a cellular repository for basic mechanistic and translational (drug compound testing) studies.