Journal
CELL
Volume 167, Issue 5, Pages 1415-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.10.042
Keywords
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Categories
Funding
- NIH Research Cambridge Biomedical Research Centre [RG64219]
- NHS Health Education England
- BLUEPRINT Grant [HEALTH-F5-2011-282510]
- BHF Cambridge Centre of Excellence [RE/13/6/30180]
- MRC CASE Industrial studentship [G66840]
- Pfizer [G73632]
- NIHR BioResource-Rare Diseases
- NIHR [RBAG163]
- European Commission [HEALTH-F2-2012-279233]
- British Heart Foundation (BHF) [RP-PG-0310-1002, RG/09/12/28096]
- Bristol Myers-Squibb
- NHSBT
- UK Medical Research Council [G0800270]
- BHF [SP/09/002]
- Cambridge Biomedical Research Centre
- European Research Council [268834]
- European Commission Framework Programme 7 [HEALTH-F2-2012-279233]
- Merck
- Pfizer
- NIHR Programme Erythropoiesis in Health and Disease [NIHR-RP-PG-0310-1004]
- Wellcome Trust [WT098051, WT091310]
- EU FP7 [HEALTH-F5-2011-282510, 257082]
- NHSBT [11-01-GEN]
- NIHR-BTRU in Donor Health and Genomics (NIHR) at the University of Cambridge [BTRU-2014-10024]
- laCaixa-Severo Ochoa pre-doctoral fellowship
- British Heart Foundation [RG/09/012/28096] Funding Source: researchfish
- Medical Research Council [MC_qA137853, 1365667, MR/L003120/1, G0800270, 1646420] Funding Source: researchfish
- National Institute for Health Research [RP-PG-0310-1004, NF-SI-0513-10151, RP-PG-0310-1002, NF-SI-0510-10214, NF-SI-0512-10014, ACF-2016-19-005] Funding Source: researchfish
- MRC [MR/L003120/1, G0800270] Funding Source: UKRI
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Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.
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