The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Abstract

SummaryMany 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.

Blood Eosinophil Count and Metabolic, Cardiac and Pulmonary Outcomes: A Mendelian Randomization Study

“…Also, in our large cohort, we showed no causal association of eosinophils with pulmonary intermediate traits (FEV 1 and FEV 1 /FVC) as determinants of pulmonary diseases pathophysiology. Our results were inconsistent with a study from the United Kingdom, which indicated significant causal associations between eosinophils and asthma, and provided evidence that eosinophils are key effector cells in the pathogenesis of asthma (Astle et al, 2016). The observed causal association in that study may be explained by a larger sample size and stronger instrumental variable (Astle et al, 2016).…”

“…Our results were inconsistent with a study from the United Kingdom, which indicated significant causal associations between eosinophils and asthma, and provided evidence that eosinophils are key effector cells in the pathogenesis of asthma (Astle et al, 2016). The observed causal association in that study may be explained by a larger sample size and stronger instrumental variable (Astle et al, 2016). Since patients with pulmonary diseases can be clinically or physiologically stratified into several subgroups (Fahy, 2015), the lack of causal associations in our study might be due to biases by subgroup stratification or possibly insufficient power to identify a relatively small causal effect of eosinophil on pulmonary outcomes in our database.…”

“…We also could not quantify any significant causal association between eosinophil count and cardiac outcomes. This result is in line with Astle et al's (2016) study, which did not find causal associations between blood cell indices, including eosinophil and cardiovascular diseases (Astle et al, 2016), using a large sample size. In our study, SH2B3-rs3184504 showed a significant association with SBP, DBP, and MAP, which was consistent with results of the International Consortium for Blood Pressure Genome-Wide Association Studies et al (2011).…”

“…factors or reverse causation, or also may be consistent with a causal role of eosinophil in these traits and diseases (Astle et al, 2016;Davey Smith & Ebrahim, 2005;Davey Smith & Hemani, 2014). If a causal association exists, then common genetic variants associated with eosinophil count may influence these complex outcomes.…”

Genomics and transcriptomics of megakaryocytes and platelets: Implications for health and disease

“…Developing clinically useful applications of all these discoveries has been challenging because some of these genetic polymorphisms can be common and associated with only slightly increased or decreased disease risk 45. However, using highly statistically powered studies, interpreting mechanisms and identifying causal alleles has become possible.…”