Genetic colocalization atlas points to common regulatory sites and genes for hematopoietic traits and hematopoietic contributions to disease phenotypes

Abstract

Background: Genetic associations link hematopoietic traits and disease end-points, but most causal variants and genes underlying these relationships are unknown. Here, we used genetic colocalization to nominate loci and genes related to shared genetic signal for hematopoietic, cardiovascular, autoimmune, neuropsychiatric, and cancer phenotypes. Methods: Our aim was to identify colocalization sites for human traits among established genome-wide significant loci. Using genome-wide association study (GWAS) summary statistics, we determined loci where multiple traits colocalized at a false discovery rate < 5%. We then identified quantitative trait loci among colocalization sites to highlight related genes. In addition, we used Mendelian randomization analysis to further investigate certain trait relationships genome-wide. Results: Our findings recapitulated developmental hematopoietic lineage relationships, identified loci that linked traits with causal genetic relationships, and revealed novel trait associations. Out of 2706 loci with genome-wide significant signal for at least 1 blood trait, we identified 1779 unique sites (66%) with shared genetic signal for 2+ hematologic traits. We could assign some sites to specific developmental cell types during hematopoiesis based on affected traits, including those likely to impact hematopoietic progenitor cells and/or megakaryocyte-erythroid progenitor cells. Through an expanded analysis of 70 human traits, we defined 2+ colocalizing traits at 2123 loci from an analysis of 9852 sites (22%) containing genome-wide significant signal for at least 1 GWAS trait. In addition to variants and genes underlying shared genetic signal between blood traits and disease phenotypes that had been previously related through Mendelian randomization studies, we defined loci and related genes underlying shared signal between eosinophil percentage and eczema. We also identified colocalizing signals in a number of clinically relevant coding mutations, including sites linking PTPN22 with Crohn's disease, NIPA with coronary artery disease and platelet trait variation, and the hemochromatosis gene HFE with altered lipid levels. Finally, we anticipate potential off-target effects on blood traits related novel therapeutic targets, including TRAIL.

Obesity and adiposity have opposing genetic impacts on human blood traits

“…Multivariable and mediation analyses on other blood traits identified cross-mediating opposing effects of WHR and BMI on quantitative blood counts across cell lineages (Figure 1d,e,f and lineages suggested that underlying mechanisms related to hematopoietic stem and progenitor cells (HSCs) common to these lineages (Thom and Voight, 2020) (Figure 1g). These findings also argued against gender-related effects: although men generally have higher hemoglobin (Vuckovic et al, 2020) and WHR (Pulit et al, 2019), women have higher platelet and neutrophil counts (Bain, 1996).…”

Body mass index and adipose distribution have opposing genetic impacts on human blood traits

“…Multivariable and mediation analyses on other blood traits identified cross-mediating opposing effects of WHR and BMI on quantitative blood counts across cell lineages (Figure 1d,e,f and lineages suggested that underlying mechanisms related to hematopoietic stem and progenitor cells (HSCs) common to these lineages (Thom and Voight, 2020) (Figure 1g). These findings also argued against sex-related effects.…”

Mechanistic and Translational Advances Using iPSC-Derived Blood Cells

“…The 3 rd definitive wave produces the hematopoietic stem cells (HSCs) that seed the fetal liver and bone marrow to ultimately yield adult-type red blood cells expressing adult hemoglobin, megakaryocyte, myeloid and lymphoid cells throughout life. In addition to the hematopoietic system, blood cells contribute to development and complex disease pathology in virtually all other organ systems [ 20 ]. For example, tissue-resident macrophages help to orchestrate tissue development, homeostasis, and repair throughout the body [ 16 , 17 ].…”

“…For example, tissue-resident macrophages help to orchestrate tissue development, homeostasis, and repair throughout the body [ 16 , 17 ]. In addition to autoimmune and cancer risks, hematopoietic cell types impact neuropsychiatric and cardiovascular disease [ 20 ].…”

“…Hematopoietic cells that impact organogenesis and pathophysiology throughout the body include tissue-resident macrophages [ 16 ]. The importance of these cells to organ (patho)physiology may be one reason that blood trait-related genes influence a myriad of complex disease states [ 20 ]. For example, yolk sac-derived monocytes migrate to the brain and differentiate into resident microglia, which thereafter comprise a lifelong self-sustained cell population ( Figure 1 ) [ 61 ].…”