Genetically influenced tobacco and alcohol use behaviors impact erythroid trait variation

• Published in: PloS one 2024-09, Vol.19 (9), p.e0309608
• Main Authors: Shivakumar, Shriya, Wilken, Madison B, Tsao, Victor, Bitarello, Bárbara D, Thom, Christopher S
• Format: Article
• Language: English
• Subjects: Alcohol Drinking - genetics; Alcohol use; Alcoholic beverages; Analysis; Anemia; Behavior; Biological activity; Biological effects; Biology and Life Sciences; Blood; Blood cell count; Blood cells; Blood levels; Blood platelets; Body mass index; Carbon monoxide; Cardiovascular disease; Cells; Chromosomes; Drinking; Drinking behavior; Drinking of alcoholic beverages; Erythrocyte Count; Erythrocytes; Erythrocytes - metabolism; Experiments; Gene loci; Genetic analysis; Genetic aspects; Genetic research; Genetic variation; Genome-wide association studies; Genome-Wide Association Study; Genomics; Glycosylated hemoglobin; Hematocrit; Hematopoiesis; Hemoglobin; Hemoglobins - genetics; Hemoglobins - metabolism; Hemopoiesis; Humans; Leukocytes; Mediation; Medicine and Health Sciences; Mendelian Randomization Analysis; Nucleotides; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Smoking; Smoking - genetics; Social Sciences; Statistics; Tobacco; Type 2 diabetes; Variation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0309608

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.