Genetically influenced tobacco and alcohol use behaviors impact erythroid trait variation

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.

Fig 1. Two sample MR effect estimates for smoking initiation (SmkInit) or alcohol use (DrnkWk) on blood traits.

(A-B) MR results using the inverse variance weighted method on five blood traits. Values for effect sizes on the indicated blood traits reflect (A) a 2-fold increase in SmkInit risk or (B) a 1 SD unit increase in alcoholic drinks per week. HGB, hemoglobin, HCT, hematocrit, RBC, red blood cell, PLT, platelet count, WBC, white blood cell count. Red indicates erythroid traits. Bars indicate 95% confidence intervals. *p<0.05.

Fig 2. Genetically predicted alcohol use mediates the genetic effect of smoking initiation on erythroid traits.

(A) By MR, an increased risk of SmkInit increases Drinks per week (DrnkWk) by inverse variance weighted (IVW), weighted media (WM), and MR Egger methods. However, increased genetically determined Drinks per week does not consistently increase SmkInit risk across MR methods. Check mark reflects MR Steiger ‘correct causal estimate’ relationship. (B) By MVMR, using an instrumental variable for SmkInit adjusted for Drinks per week, the effects of SmkInit on quantitative blood traits were nullified. Effects of Drinks per week on blood traits remain significantly negative. Bars indicate 95% confidence intervals. (C) Mediation analysis showed that SmkInit made a statistically insignificant direct effect on RBC, whereas the total effect (including indirect effects through DrnkWk) negatively impacts RBC. *p<0.05.