ABSTRACT
Genome wide association studies (GWAS) have associated thousands of loci with quantitative human blood trait variation. Loci and related genes that impact blood trait variation may regulate blood cell-intrinsic biological processes, or alternatively impact blood cell development and function via systemic factors. Clinical observations have linked tobacco or alcohol use with altered blood traits, but these trait relationships have not been systematically explored at the genetic level. Applying a Mendelian randomization (MR) framework to GWAS summary statistics, we explore relationships between smoking and drinking behaviors with 15 quantitative blood traits. We find that the effects of smoking and drinking are confined to red blood cell traits. An instrumental variable (IV) comprised of 113 single nucleotide polymorphisms (SNPs) associated with smoking initiation is associated with decreased hemoglobin (HGB: Effect = -0.07 standard deviation units [95% confidence interval = -0.03 to -0.10 SD units], P = 1x10-4), hematocrit (HCT: Effect = -0.06 [-0.03 - -0.09] SD units, P = 4x10-4), and red blood cell count (RBC: Effect = -0.05 [-0.02 - -0.09] SD units, P = 5x10-3) without impacting platelet count (P = 0.9) or white blood cell count (P = 0.6). Similarly, an IV associated with an increased number of alcoholic drinks consumed per week is associated with decreased HGB (Effect = -0.22 [-0.42 - -0.02] SD units, P = 3x10-2) and RBC (Effect = -0.27 [-0.51 - -0.03] SD units, P = 3x10-2). Using multivariable MR and causal mediation analyses, we find that an increased genetic predisposition to smoking initiation is associated with increased alcohol intake, and that alcohol use mediates the genetic effect of smoking initiation on red blood cell traits. These findings demonstrate a novel role for genetically influenced behaviors on human blood traits, revealing opportunities to dissect related pathways and mechanisms that influence hematopoiesis and blood cell biology.
Subject(s)
Alcohol Drinking , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Humans , Alcohol Drinking/genetics , Mendelian Randomization Analysis , Hemoglobins/metabolism , Hemoglobins/genetics , Smoking/genetics , Erythrocytes/metabolism , Quantitative Trait Loci , Erythrocyte Count , HematocritABSTRACT
Tropomyosins coat actin filaments to impact actin-related signaling and cell morphogenesis. Genome-wide association studies have linked Tropomyosin 1 (TPM1) with human blood trait variation. TPM1 has been shown to regulate blood cell formation in vitro, but it remains unclear how or when TPM1 affects hematopoiesis. Using gene-edited induced pluripotent stem cell (iPSC) model systems, we found that TPM1 knockout augmented developmental cell state transitions and key signaling pathways, including tumor necrosis factor alpha (TNF-α) signaling, to promote hemogenic endothelial (HE) cell specification and hematopoietic progenitor cell (HPC) production. Single-cell analyses revealed decreased TPM1 expression during human HE specification, suggesting that TPM1 regulated in vivo hematopoiesis via similar mechanisms. Analyses of a TPM1 gene trap mouse model showed that TPM1 deficiency enhanced HE formation during embryogenesis, without increasing the number of hematopoietic stem cells. These findings illuminate novel effects of TPM1 on developmental hematopoiesis.
ABSTRACT
Genome wide association studies (GWAS) have associated thousands of loci with quantitative human blood trait variation. Blood trait associated loci and related genes may regulate blood cell-intrinsic biological processes, or alternatively impact blood cell development and function via systemic factors and disease processes. Clinical observations linking behaviors like tobacco or alcohol use with altered blood traits can be subject to bias, and these trait relationships have not been systematically explored at the genetic level. Using a Mendelian randomization (MR) framework, we confirmed causal effects of smoking and drinking that were largely confined to the erythroid lineage. Using multivariable MR and causal mediation analyses, we confirmed that an increased genetic predisposition to smoke tobacco was associated with increased alcohol intake, indirectly decreasing red blood cell count and related erythroid traits. These findings demonstrate a novel role for genetically influenced behaviors in determining human blood traits, revealing opportunities to dissect related pathways and mechanisms that influence hematopoiesis.
ABSTRACT
Tropomyosins coat actin filaments and impact actin-related signaling and cell morphogenesis. Genome-wide association studies have linked Tropomyosin 1 (TPM1) with human blood trait variation. Prior work suggested that TPM1 regulated blood cell formation in vitro, but it was unclear how or when TPM1 affected hematopoiesis. Using gene-edited induced pluripotent stem cell (iPSC) model systems, TPM1 knockout was found to augment developmental cell state transitions, as well as TNFα and GTPase signaling pathways, to promote hemogenic endothelial (HE) cell specification and hematopoietic progenitor cell (HPC) production. Single-cell analyses showed decreased TPM1 expression during human HE specification, suggesting that TPM1 regulated in vivo hematopoiesis via similar mechanisms. Indeed, analyses of a TPM1 gene trap mouse model showed that TPM1 deficiency enhanced the formation of HE during embryogenesis. These findings illuminate novel effects of TPM1 on developmental hematopoiesis.