Mitochondrial related genome-wide Mendelian randomization identifies putatively causal genes for multiple cancer types

Abstract

Background: Mitochondrial dysfunction is a hallmark of cancer. However, it is unclear whether it is a cause of cancer. This two-sample Mendelian randomization (MR) analyses, uses genetic instruments to proxy the exposure of mitochondrial dysfunction and cancer summary statistics as outcomes, allowing for causal inferences.

Methods: Summary statistics from 18 common cancers (2107-491,974 participants), gene expression, DNA methylation and protein expression quantitative trait loci (eQTL, mQTL and pQTL, respectively, 1000-31,684 participants) on individuals of European ancestry, were included. Genetic variants located within or close to the 1136 mitochondrial-related genes (in cis) and robustly associated with the mitochondrial molecular alterations were used as instrumental variables, and their causal associations with cancers were examined using summary-data-based MR (SMR) analyses. An additional five MR methods were used as sensitivity analyses to confirm the casual associations. A Bayesian test for colocalization between mitochondrial molecular QTLs and cancer risk loci was performed to provide insights into the potential regulatory mechanisms of risk variants on cancers.

Findings: We identified potential causal relationships between mitochondrial-related genes and breast, prostate, gastric, lung cancer and melanoma by primary SMR analyses. The sensitivity and the colocalization analyses further refined four genes that have causal effects on three types of cancer. We found strong evidence of positive association of FDPS expression level with breast cancer risk (OR per SD, 0.66; 95% CI, 0.49-0.83; P = 9.77 × 10^-7), NSUN4 expression level with both breast cancer risk (OR per SD, 1.05; 95% CI, 1.03-1.07; P = 5.24 × 10^-6) and prostate cancer risk (OR per SD, 1.06; 95% CI, 1.03-1.09; P = 1.01 × 10^-5), NSUN4 methylation level with both breast and prostate cancer risk, and VARS2 methylation level with lung cancer risk.

Interpretations: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in multiple cancers. Furthermore, this study identified candidate genes that can be the targets of potential pharmacological agents for cancer prevention.

Funding: This work was supported by Styrelsen för Allmänna Sjukhusets i Malmö Stiftelse för bekämpande av cancer (20211025).

Keywords: Cancers; Colocalization; Mendelian randomization; Mitochondrial dysfunction; Pharmaceutical targets.

Fig. 1

Flowchart of the analyses performed.

Fig. 2

Mendelian randomization results for the association between the expression of mitochondrial genes and cancer risk.^aRepresents the effect size (β) of a variant on mRNA expressions. β > 0 means positive association, and β < 0 means negative association. ^bOdd ratios were calculated by the expectation of causal estimate (β coefficient). ^c‘Colocalization’ indicates PP.H4 between eQTLs and cancer outcomes. PP.H4 > 0.8 is the well-applied cut-off for the evidence of colocalization.

Fig. 3

Mendelian randomization results for the association between mitochondrial gene methylations and cancer risk.^aRepresents the effect size (β) of a variant on DNA methylation. β > 0 means positive association, and β < 0 means negative association. ^bOdd ratios were calculated by the expectation of causal estimate (β coefficient). ^c‘Colocalization’ indicates PP.H4 between mQTLs and cancer outcomes. PP.H4 > 0.8 is the well-applied cut-off for the evidence of colocalization.