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Genetic variants associated with platelet count are predictive of human disease and physiological markers.

ABSTRACT: Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease.

SUBMITTER: Mikaelsdottir E

PROVIDER: S-EPMC8476563 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Genetic variants associated with platelet count are predictive of human disease and physiological markers.

Mikaelsdottir Evgenia E Thorleifsson Gudmar G Stefansdottir Lilja L Halldorsson Gisli G Sigurdsson Jon K JK Lund Sigrun H SH Tragante Vinicius V Melsted Pall P Rognvaldsson Solvi S Norland Kristjan K Helgadottir Anna A Magnusson Magnus K MK Ragnarsson Gunnar B GB Kristinsson Sigurdur Y SY Reykdal Sigrun S Vidarsson Brynjar B Gudmundsdottir Ingibjorg J IJ Olafsson Isleifur I Onundarson Pall T PT Sigurdardottir Olof O Sigurdsson Emil L EL Grondal Gerdur G Geirsson Arni J AJ Geirsson Gudmundur G Gudmundsson Julius J Holm Hilma H Saevarsdottir Saedis S Jonsdottir Ingileif I Thorgeirsson Gudmundur G Gudbjartsson Daniel F DF Thorsteinsdottir Unnur U Rafnar Thorunn T Stefansson Kari K

Communications biology 20210927 1

Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between pla ...[more]

PMID: 34580418

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Project description:Especially for pediatric patients, proxies of mucosal inflammation are needed. The Pediatric Ulcerative Colitis Activity Index (PUCAI) has been established to predict clinical and endoscopic disease activity. However, histologic inflammation might persist. We applied a special variable selection technique to predict histologic healing in pediatric ulcerative colitis (UC) as parsimoniously (but still as precisely) as possible. The retrospective analysis included data from two study cohorts, comprising 91 visits from 59 pediatric patients with UC. A Bayesian ordinal regression model was used in combination with a projection-predictive feature selection (PPFS) to identify a minimal subset of clinical and laboratory parameters sufficient for the prediction of histologic disease activity. Following the PPFS, CEDATA-GPGE patient registry data were analyzed to investigate the relevance of the selected predictors in relation to PUCAI and Physician Global Assessment (PGA) in up to 6697 patient visits. Fecal calprotectin (FC) and platelet count were identified as the minimal subset of predictors sufficient for prediction of histologic disease activity in pediatric UC. FC and platelet count also appeared to be associated with increasing disease activity as measured by PUCAI and PGA in the CEDATA-GPGE registry. Based on the selected model, predictions can be performed with a Shiny web app. Conclusion: Our statistical approach constitutes a reproducible and objective tool to select a minimal subset of the most informative parameters to predict histologic inflammation in pediatric UC. A Shiny app shows how physicians may predict the histologic activity in a user-friendly way using FC and platelet count. To generalize the findings, further prospective studies will be needed. What is Known: • Histologic healing is a major endpoint in the therapy of ulcerative colitis (UC). • The PUCAI score has been established to predict disease activity in pediatric UC but is not suitable for the prediction of histologic healing. What is New: • Our Bayesian ordinal regression model in combination with a projection-predictive feature selection is a reproducible and objective tool to select the minimal subset of clinical and laboratory parameters to predict histologic inflammation in pediatric UC. • Histologic inflammation in pediatric UC can be non-invasively predicted based on the combination of fecal calprotectin levels and platelet count.

Project description:Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized genetic variants associated with MPV and PLT using functional, pathway and disease enrichment analyses; we assessed pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic network had data for PLT and 6,291 participants had data for MPV. We identified five chromosomal regions associated with PLT and eight associated with MPV at genome-wide significance (P < 5E-8). In addition, we replicated 20 SNPs [out of 56 SNPs (α: 0.05/56 = 9E-4)] influencing PLT and 22 SNPs [out of 29 SNPs (α: 0.05/29 = 2E-3)] influencing MPV in a published meta-analysis of GWAS of PLT and MPV. While our GWAS did not find any new associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development, and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1,368 diagnoses (0.05/1368 = 3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune, and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.

Dataset Information

Genetic variants associated with platelet count are predictive of human disease and physiological markers.

Publications

Genetic variants associated with platelet count are predictive of human disease and physiological markers.

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