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. We are currently pursuing further biochemical work on GRK5 and Grk5 knockout mice (collaboration with Craig Morrel/Rochester). 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 recently accepted for publication in the leading cardiovascular research journal Circulation. 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). 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). 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. 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. Component 3: Development and Application of Bioinformatics Resources and New Public Repository for COVID-19 Genetics. Beyond the eQTL database mentioned above, a large genome-wide association study (GWAS) results database GRASP continues to be updated, and an online NIH query site developed. The database is publicly downloadable and queryable at the URL: grasp.nhlbi.nih.gov/Overview.aspx. One of the main features of the database utilized by researchers worldwide is the posting of full GWAS summary statistics where available. There are now >150 studies with such full GWAS data posted for researchers worldwide to access and utilize, with several more coming. The database was widely used in addressing many research questions as evidenced by thousands of web hits and queries per month and 575+ citations to GRASP-related publications. In May 2020, in response to the COVID-19 crisis we began GWAS analysis of COVID-19 susceptibility utilizing our approved access to the UK Biobank data. With permission of the UK Biobank we established a COVID-19 GWAS posting page (https://grasp.nhlbi.nih.gov/Covid19GWASResults.aspx). With each new release we rapidly analyze case data against >47 million genetic variants utilizing the NIH Biowulf supercomputing cluster. Rather than trying to publish these results we chose to rapidly publicly post these to maximally benefit the scientific research community. We have also re-posted other scientific data on GWAS of COVID-19 traits now encompassing multiple other GWAS studies including COVID-hgi, GENOMICC and the CORCORONA trial. We provide deep bioinformatics annotations of the top results of each of these studies. Web metrics for GRASP indicate this COVID-19 site is seeing a high amount of traffic and downloads, across the life of the database seeing >12,000 visits and downloads. Novel analyses of the COVID-19 GWAS data across the pandemic trajectory and releases have led to interesting insights into the changing demographics of affected cases (e.g., by age, ancestry and diabetes status), and have suggested additional genetic susceptibility loci. This and the database resource are summarized in a manuscript that was published in 2022 (Thibord et al., HGG).