Dataset Information

The effects of pathogenic and likely pathogenic variants for inherited hemostasis disorders in 140 214 UK Biobank participants.

ABSTRACT: Rare genetic diseases affect millions, and identifying causal DNA variants is essential for patient care. Therefore, it is imperative to estimate the effect of each independent variant and improve their pathogenicity classification. Our study of 140 214 unrelated UK Biobank (UKB) participants found that each of them carries a median of 7 variants previously reported as pathogenic or likely pathogenic. We focused on 967 diagnostic-grade gene (DGG) variants for rare bleeding, thrombotic, and platelet disorders (BTPDs) observed in 12 367 UKB participants. By association analysis, for a subset of these variants, we estimated effect sizes for platelet count and volume, and odds ratios for bleeding and thrombosis. Variants causal of some autosomal recessive platelet disorders revealed phenotypic consequences in carriers. Loss-of-function variants in MPL, which cause chronic amegakaryocytic thrombocytopenia if biallelic, were unexpectedly associated with increased platelet counts in carriers. We also demonstrated that common variants identified by genome-wide association studies (GWAS) for platelet count or thrombosis risk may influence the penetrance of rare variants in BTPD DGGs on their associated hemostasis disorders. Network-propagation analysis applied to an interactome of 18 410 nodes and 571 917 edges showed that GWAS variants with large effect sizes are enriched in DGGs and their first-order interactors. Finally, we illustrate the modifying effect of polygenic scores for platelet count and thrombosis risk on disease severity in participants carrying rare variants in TUBB1 or PROC and PROS1, respectively. Our findings demonstrate the power of association analyses using large population datasets in improving pathogenicity classifications of rare variants.

SUBMITTER: Stefanucci L

PROVIDER: S-EPMC10733830 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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The effects of pathogenic and likely pathogenic variants for inherited hemostasis disorders in 140 214 UK Biobank participants.

Stefanucci Luca L Collins Janine J Sims Matthew C MC Barrio-Hernandez Inigo I Sun Luanluan L Burren Oliver S OS Perfetto Livia L Bender Isobel I Callahan Tiffany J TJ Fleming Kathryn K Guerrero Jose A JA Hermjakob Henning H Martin Maria J MJ Stephenson James J Paneerselvam Kalpana K Petrovski Slavé S Porras Pablo P Robinson Peter N PN Wang Quanli Q Watkins Xavier X Frontini Mattia M Laskowski Roman A RA Beltrao Pedro P Di Angelantonio Emanuele E Gomez Keith K Laffan Mike M Ouwehand Willem H WH Mumford Andrew D AD Freson Kathleen K Carss Keren K Downes Kate K Gleadall Nick N Megy Karyn K Bruford Elspeth E Vuckovic Dragana D

Blood 20231201 24

Rare genetic diseases affect millions, and identifying causal DNA variants is essential for patient care. Therefore, it is imperative to estimate the effect of each independent variant and improve their pathogenicity classification. Our study of 140 214 unrelated UK Biobank (UKB) participants found that each of them carries a median of 7 variants previously reported as pathogenic or likely pathogenic. We focused on 967 diagnostic-grade gene (DGG) variants for rare bleeding, thrombotic, and plate ...[more]

PMID: 37647632

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Dataset Information

The effects of pathogenic and likely pathogenic variants for inherited hemostasis disorders in 140 214 UK Biobank participants.

Publications

The effects of pathogenic and likely pathogenic variants for inherited hemostasis disorders in 140 214 UK Biobank participants.

Similar Datasets

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