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 each carries a median of 7 variants previously reported as pathogenic or likely pathogenic. We focused on 967 diagnostic-grade genes (DGGs) 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.
| Original language | English |
|---|---|
| Pages (from-to) | 2055-2068 |
| Number of pages | 14 |
| Journal | Blood |
| Volume | 142 |
| Issue number | 24 |
| Early online date | 30 Aug 2023 |
| DOIs | |
| Publication status | Published - 14 Dec 2023 |
Bibliographical note
Funding Information:Research in the Ouwehand laboratory received funding from the British Heart Foundation (BHF), the International Society on Thrombosis and Haemostasis , Medical Research Council (MRC), National Health Service Blood and Transplant , and the NIHR . For his PhD period, L. Stefanucci was supported by the BHF grant from the Cambridge BHF Centre of Research Excellence (RE/18/1/34212); J.C. and M.C.S. were awarded MRC Clinical Research Training Fellowships (MR/P02002X/1 and MR/R002363/1, respectively). K. Freson was supported by the Research Council of the University of Leuven (Special Research Fund [BOF] KU Leuven, Belgium, C14/19/096) and by an unrestricted grant of Sobi . L.P., H.H., K.P., and P.P. received funding from European Molecular Biology Laboratory core funding, Open Targets (grant agreements OTAR-044 , OTAR02-048 , OTAR02-066 ) and the Wellcome Trust grant 212925/Z/18/Z . P.B. is supported by the Helmut Horten Stiftung and the ETH Zurich Foundation . W.H.O. is a senior investigator of the NIHR. D.V. is a member of the Health Protection Research Unit in Chemical and Radiation Threats and Hazards, a partnership between Public Health England and Imperial College London which is funded by the NIHR. M.F. is supported by the BHF ( FS/18/53/33863 ) and by the National Institute for Health and Care Research Exeter Biomedical Research Centre . E.B. is supported by National Human Genome Research Institute grant U24HG003345 & Wellcome Trust grant 208349/Z/17/Z . T.J.C. was supported by funding from the National Library of Medicine (NLM T15LM009451 and T15LM007079).
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