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. 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.

Keywords: Blood; Erythroid; Genetics; Mendelian randomization.

Figure 1.. Smoking initiation (SmkInit) and alcohol use (Drinks) negatively impact genetically determined hemoglobin (HGB), hematocrit (HCT), and red blood cell count (RBC).

(A-B) MR results using the inverse variance weighted method are shown, with values for Effect sizes on the indicated blood traits reflecting (A) a 2-fold increase in SmkInit risk or (B) a 1 SD unit increase in alcoholic drinks per week. PLT, platelet count. WBC, white blood cell count. Bars indicate 95% confidence intervals. *p<0.05.

Figure 2.. Genetically predicted alcohol use mediates the effects of smoking behavior on erythroid traits.

(A) By MR, increased risk of SmkInit increases Drinks per week (Drinks) 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. (C) Mediation analysis showed that SmkInit made a statistically insignificant effect on RBC, whereas the total effect (including indirect effects through Drinks per week) significantly negatively impacts RBC. Bars indicate 95% confidence intervals. *p<0.05.