Mendelian Randomization and GWAS Meta Analysis Revealed the Risk-Increasing Effect of Schizophrenia on Cancers

Abstract

The causal relationship between cancer and Schizophrenia (SCZ) remains controversial. Some researchers have found that SCZ is a cancer-preventive factor in cohort studies or meta-analyses, whereas others have found the opposite. To understand more about this issue, we used two-sample Mendelian randomization (2SMR) on available GWAS summary results to evaluate potential genetic connections between SCZ and 13 cancers. We discovered that the genetic susceptibility to schizophrenia lead to an increasing risk of breast cancer (odds ratio [OR] per log-odds increase in schizophrenia risk: 1.049, 95% confidence interval [CI]:1.023–1.075; p = 0.00012; FDR = 0.0017), ovarian cancer (OR, 1.326; 95% CI, 1.267–1.387; p = 0.0007; FDR = 0.0045), and thyroid cancer (OR, 1.575; 95% CI, 1.048–2.365; p = 0.0285; FDR = 0.123). Secondly, we performed a meta-analysis based on the GWAS summary statistics of SCZ and the three significant cancers. Next, we associated genetic variants to genes using two gene mapping strategies: (a) positional mapping based on genomic proximity and (b) expression quantitative trait loci (eQTL) mapping based on gene expression linkage across multiple tissues. As a result, we identified 114 shared loci and 437 shared genes in three groups, respectively. Functional enrichment analysis shows that the most enriched biological pathways are related to epigenetic modification. In addition, we noticed that SCZ would affect the level of thyroid-stimulating hormone (OR, 1.095; 95% CI, 1.006–1.191; p = 0.0354; FDR = 0.177), which may further affect the level of estrogen and the risk of the above three cancers. In conclusion, our findings under the 2SMR assumption provide crucial insights into the risk-increasing effect of SCZ on three cancers’ risk. Furthermore, these results may provide insights into understanding the genetic predisposition and underlying biological pathways of comorbid SCZ and cancers.

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

“…Our study investigate the causal links between seven psychiatric disorders and the risks of breast cancer, breast benign tumors, and breast inflammatory diseases using MR analyses for the first time. When the GWAS data for psychiatric disorders were derived from the PGC, schizophrenia and major depressive disorder were demonstrated to significantly increase the risk of overall breast cancer based on the two-sample MR analyses, in line with previous researches (16,37). We stratified the analyses based on the ER status of breast cancer, since the pathogenesis and responses to treatments differ for each pathological state.…”

“…where EAF was the effector allele frequency, β was the effector size, N was the sample size and se (β) was the standard error of the genetic effect. And then we calculated the F statistic: F = [R 2 × (N-k-1)]/ [(1-R 2 ) × k], assessing the strength of the statistics (24,28,29), in which k was the number of instrumental variables (16). SNPs with F < 10 that were considered weak instrumental variables had been discarded (18).…”

“…Mendelian randomization (MR) is a promising causal reasoning device developed in current years (13,14), which makes use of genetic variations intently associated with exposures as instrumental variables to discover causal relationships between exposures and outcomes (14)(15)(16). The MR analysis is counted on natural random classifications of genetic variations (17,18).…”

Adenosine, Schizophrenia and Cancer: Does the Purinergic System Offer a Pathway to Treatment?

“…Interestingly, breast cancer incidence rates are consistently higher in studies of schizophrenia populations ( Table 1 ). Recent genome wide association studies (GWAS) have identified a shared risk locus associated with schizophrenia and breast cancer [ 24 ] and increased risk for breast, ovarian and thyroid cancers, but not other cancers, in schizophrenia patients [ 25 ]. Conversely, lung, liver and prostate cancer incidence appears to be lower in schizophrenia populations ( Table 1 ), suggesting that incidence rates of some cancers may be reduced, or unchanged, in these patients.…”

Causal associations between schizophrenia and cancers risk: a Mendelian randomization study

“…Previous MR studies have shown a positive association between schizophrenia and the risk of ovarian, thyroid and breast cancers ( 13 ). However, in contrast to clinical observations, patients with schizophrenia may be at greater risk for other cancers, such as lung cancer.…”