Major depression disorder may causally associate with the increased breast cancer risk: Evidence from two-sample mendelian randomization analyses

Abstract

Introduction: Major depression disorder (MDD) has been associated with increased breast cancer risk in epidemiological studies; however, it is still unknown whether this association is causal or not. The aim of this study is to determine the causal relationship between MDD and breast cancer risk.

Methods: Two-sample Mendelian randomization (MR) analyses with 92 single-nucleotide polymorphisms (SNPs) significantly associated with MDD as instrumental variables (IVs) were performed. Effects of these SNPs on breast cancer in women were estimated in the Breast Cancer Association Consortium (122,977 cases and 105,974 controls) using inverse variance weighted (IVW), weighted median and multivariable MR models. Heterogeneity and pleiotropy effects were assessed based on IVW and MR-Egger regression model, respectively.

Results: An 8.7% increased risk of overall breast cancer [odds ratio (OR) = 1.087; 95% confidence interval (CI) 1.011-1.170; P = 0.025] per log-odds ratio increment of MDD risk based on the IVW model was noticed. Similar results were obtained with the multivariable MR model (OR = 1.118, 95% CI = 1.010-1.237; P = 0.031). An increment but not statistically significant causality association was noticed between MDD and risk of ER+ (OR = 1.098, 95% CI = 0.984-1.227; P = 0.093) or ER- (OR = 1.129, 95% CI = 0.982-1.297; P = 0.089) breast cancer under multivariable MR model. No significant pleiotropy effects were observed for the IVs in the two-sample MR studies.

Conclusions: The results suggested that a genetic predisposition of MDD is causally associated with overall breast cancer risk; however, the underlying biological mechanisms are worthy of further study.

Keywords: breast cancer; major depression disorder; mendelian randomization; single-nucleotide polymorphism.

FIGURE 1

The study assumptions of the two‐sample Mendelian Randomization analysis between MDD and breast cancer. The assumptions including: (1) the genetic instrumental variables (IVs) should be significantly associated with MDD; (2) the genetic IVs should not be associated with other exposure‐results confounding factors; (3) the genetic IVs must only be through MDD and not through any other confounders to influence the breast cancer risk. The dotted lines indicate violate of the assumptions. BCAC, Breast Cancer Association Consortium; ER, Estrogen Receptor; GSCAN, GWAS and Sequencing Consortium of Alcohol and Nicotine use; MRC‐IEU, MRC Integrative Epidemiology Unit; PGC, Psychiatric Genomics Consortium; ReproGen, Reproductive Genetics Consortium; SSGAC, Social Science Genetic Association Consortium.

FIGURE 2

Forest plot of the two‐sample MR analysis results between MDD and the risk of breast cancer using conventional inverse variance weighted (IVW) and weighted median methods. Each black dot and horizontal line represented the causal effect obtained by Wald ratio method and 95% CI for individual IV, respectively. The red dots and horizontal lines at the bottom represent the overall causal effects obtained by different methods and 95% CI, respectively. X‐axis is shown in natural logarithmic scale.