Is Schizophrenia a Risk Factor for Breast Cancer?

Evidence From Genetic Data

Enda M. Byrne; Manuel A. R. Ferreira; Angli Xue; Sara Lindström; Xia Jiang; Jian Yang; Douglas F. Easton; Naomi R. Wray; Georgia Chenevix-Trench

Disclosures

Schizophr Bull. 2019;45(6):1251-1256. 

In This Article

Abstract and Introduction

Abstract

Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very large genome-wide association studies of schizophrenia (n = 40675 cases and 64643 controls) and breast cancer (n = 122977 cases and 105974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship. Using LD-score regression, we found that there is a small but significant genetic correlation (rG) between the 2 disorders (rG = 0.14, SE = 0.03, P = 4.75 × 10−8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (SE = 0.009, P = 2.3 × 10−4). A 1 SD increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = −0.005, SE = 0.012, P = .67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results. These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship.

Introduction

Individuals diagnosed with schizophrenia have increased mortality compared to the general population with a life expectancy of 10–15 years less than those without the disorder.[1] Despite having increased levels of risk factors for cancer such as smoking and physical inactivity, epidemiological studies have found evidence that the age-specific incidence rates of most cancers are lower in patients with schizophrenia compared to the general population.[2] Breast cancer is an exception to this trend, with several studies showing increased risk in women with schizophrenia. A systematic review of 13 studies found that 6 studies observed an increased risk in schizophrenia patients,[3] and the 3 largest studies estimated standardized incidence ratios (SIR) of 1.11 (1.00–1.22),[4] 1.20 (1.05–1.38)[5] and 1.15 (0.98–1.34).[6] More recently, a study of insurance claims data in Taiwan found that the risk of breast cancer in female schizophrenia patients after adjustment for confounders was 1.94 (95% CI: 1.43–2.63).[7] A meta-analysis including data from 125760 women estimated an SIR of 1.31 (95% CI: 1.14–1.50).[8]

The mechanism behind the increased rate of breast cancer among schizophrenia patients is unknown. A key question of interest is if the relationship is due to shared genetic and/or lifestyle risk factors or a consequence of the disease itself (eg, related to the disease process or treatment). Here, we use genome-wide association study (GWAS) summary statistics results to investigate the genetic relationship between schizophrenia and breast cancer. First, we investigate if there is a genetic correlation (rG) between the 2 disorders using single nucleotide polymorphisms (SNPs) throughout the genome. Second, we investigate if there is evidence of a causal relationship between the 2 disorders using Mendelian Randomization (MR).[9]

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