An exploration of the correlations between seven psychiatric disorders and the risks of breast cancer, breast benign tumors and breast inflammatory diseases: Mendelian randomization analyses

Abstract

Background: Previous observational studies have showed that certain psychiatric disorders may be linked to breast cancer risk, there is, however, little understanding of relationships between mental disorders and a variety of breast diseases. This study aims to investigate if mental disorders influence the risks of overall breast cancer, the two subtypes of breast cancer (ER+ and ER-), breast benign tumors and breast inflammatory diseases.

Methods: During our research, genome-wide association study (GWAS) data for seven psychiatric disorders (schizophrenia, major depressive disorder, bipolar disorder, post-traumatic stress disorder, panic disorder, obsessive-compulsive disorder and anorexia nervosa) from the Psychiatric Genomics Consortium (PGC) and the UK Biobank were selected, and single-nucleotide polymorphisms (SNPs) significantly linked to these mental disorders were identified as instrumental variables. GWAS data for breast diseases came from the Breast Cancer Association Consortium (BCAC) as well as the FinnGen consortium. We performed two-sample Mendelian randomization (MR) analyses and multivariable MR analyses to assess these SNPs' effects on various breast diseases. Both heterogeneity and pleiotropy were evaluated by sensitivity analyses.

Results: When the GWAS data of psychiatric disorders were derived from the PGC, our research found that schizophrenia significantly increased the risks of overall breast cancer (two-sample MR: OR 1.05, 95%CI [1.03-1.07], p = 3.84 × 10^-6; multivariable MR: OR 1.06, 95%CI [1.04-1.09], p = 2.34 × 10^-6), ER+ (OR 1.05, 95%CI [1.02-1.07], p = 5.94 × 10^-5) and ER- (two-sample MR: OR 1.04, 95%CI [1.01-1.07], p = 0.006; multivariable MR: OR 1.06, 95%CI [1.02-1.10], p = 0.001) breast cancer. Nevertheless, major depressive disorder only showed significant positive association with overall breast cancer (OR 1.12, 95%CI [1.04-1.20], p = 0.003) according to the two-sample MR analysis, but not in the multivariable MR analysis. In regards to the remainder of the mental illnesses and breast diseases, there were no significant correlations. While as for the data from the UK Biobank, schizophrenia did not significantly increase the risk of breast cancer.

Conclusions: The correlation between schizophrenia and breast cancer found in this study may be false positive results caused by underlying horizontal pleiotropy, rather than a true cause-and-effect relationship. More prospective studies are still needed to be carried out to determine the definitive links between mental illnesses and breast diseases.

Keywords: breast benign tumors; breast cancer; breast inflammatory diseases; mendelian randomization; psychiatric disorders.

Figure 1

Causal associations between seven psychiatric disorders and the risks of breast diseases: Results of MR analyses using the IVW method. (A) Overall breast cancer; (B) ER+ breast cancer; (C) ER− breast cancer; (D) Breast benign tumors; (E) Breast inflammatory diseases.

Figure 2

Scatter plots for the effects of schizophrenia and major depressive disorder on the risk of breast cancer. (A) Causal relationship between schizophrenia and overall breast cancer; (B) Causal relationship between major depressive disorder and overall breast cancer; (C) Causal relationship between schizophrenia and ER+ breast cancer; (D) Causal relationship between major depressive disorder and ER+ breast cancer; (E) Causal relationship between schizophrenia and ER− breast cancer; (F) Causal relationship between major depressive disorder and ER− breast cancer.

Figure 3

The results of multivariable MR analyses. (A) The outcome was overall breast cancer; (B) The outcome was ER- breast cancer.