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2023 Feb; 88: 104432.
电子生物医学。2023年2月;88: 104432.
Published online 2023 Jan 10. doi: 10.1016/j.ebiom.2022.104432
PMCID: PMC9841346 PMCID:PMC9841346
PMID: 36634566 PMID:36634566

Mitochondrial related genome-wide Mendelian randomization identifies putatively causal genes for multiple cancer types
线粒体相关全基因组孟德尔随机化可识别多种癌症类型的假定致病基因

Yanni Li,a, Kristina Sundquist,a,b,c,d Naiqi Zhang,a Xiao Wang,a Jan Sundquist,a,b,c,d and Ashfaque A. Memona
Yanni Li、 a, Kristina Sundquist、 a, b, c, d Naiqi Zhang、 a Xiao Wang、 a Jan Sundquist a, b, c, d 和 Ashfaque A. Memon a

Associated Data 相关数据

Supplementary Materials 补充材料

Summary 总结

Background 背景

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.
线粒体功能障碍是癌症的标志。然而,目前尚不清楚它是否是癌症的原因。这种双样本孟德尔随机化 (MR) 分析使用遗传仪器将线粒体功能障碍的暴露和癌症汇总统计数据代理为结果,从而可以进行因果推断。

Methods 方法

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.
包括来自18种常见癌症(2107-491,974名受试者)、基因表达、DNA甲基化和蛋白质表达数量性状位点(分别为eQTL、mQTL和pQTL,1000-31,684名受试者)的汇总统计数据。位于 1136 个线粒体相关基因(顺式)内或附近的遗传变异与线粒体分子改变密切相关,用作工具变量,并使用基于汇总数据的 MR (SMR) 分析检查它们与癌症的因果关系。另外五种MR方法被用作敏感性分析,以确认偶然关联。对线粒体分子QTL和癌症风险位点之间的共定位进行了贝叶斯检验,以深入了解癌症风险变异的潜在调控机制。

Findings 发现

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.
我们通过初级SMR分析确定了线粒体相关基因与乳腺癌、前列腺癌、胃癌、肺癌和黑色素瘤之间的潜在因果关系。敏感性和共定位分析进一步完善了对三种癌症有因果关系的四个基因。我们发现了FDPS表达水平与乳腺癌风险呈正相关的有力证据(OR标准差,0.66;95%CI,0.49-0.83;P = 9.77 × 10 −7 ),NSUN4 表达水平与乳腺癌风险(OR per SD,1.05;95% CI,1.03–1.07;P = 5.24 × 10 −6 ) 和前列腺癌风险(OR 根据 SD,1.06;95% CI,1.03–1.09;P = 1.01 × 10 −5 ),NSUN4 甲基化水平与乳腺癌和前列腺癌风险相关,VARS2 甲基化水平与肺癌风险相关。

Interpretations 解释

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.
这项数据驱动的 MR 研究证明了线粒体功能障碍在多种癌症中的因果作用。此外,这项研究还确定了候选基因,这些候选基因可以作为预防癌症的潜在药物的靶标。

Funding 资金

This work was supported by Styrelsen för Allmänna Sjukhusets i Malmö Stiftelse för bekämpande av cancer (20211025).
这项工作得到了马尔默总医院癌症预防基金会(20211025)董事会的支持。

Keywords: Mendelian randomization, Mitochondrial dysfunction, Cancers, Colocalization, Pharmaceutical targets
关键词:孟德尔随机化, 线粒体功能障碍, 癌症, 共定位, 药物靶点
Abbreviations: MR, Mendelian randomization; SMR, Summary-data-based MR; MtDNA, Mitochondrial DNA; IVs, Instrumental variables; GWAS, Genome-wide association studies; SNPs, Single nucleotide polymorphisms; eQTL, Expression quantitative trait loci; mQTL, Methylation quantitative trait loci; pQTL, Protein quantitative trait loci; HEIDI, Heterogeneity independent instruments; LD, Linkage disequilibrium; CpG, Cytosine-guanine dinucleotides; IVW, Inverse variance weighting; MR-PRESSO, MR Pleiotropy Residual Sum and Outlier
缩写:MR,孟德尔随机化;SMR,基于汇总数据的MR;MtDNA,线粒体DNA;IVs, 工具变量;GWAS,全基因组关联研究;SNPs, 单核苷酸多态性;eQTL: 表达数量性状位点;mQTL, 甲基化数量性状位点;pQTL: 蛋白质数量性状位点;HEIDI,异质性独立仪器;LD: 联动不平衡;CpG,胞嘧啶-鸟嘌呤二核苷酸;IVW, 反方差加权;MR-PRESSO, MR 多效性残差和异常值

Research in context 情境研究

Evidence before this study
本研究前的证据

Previous studies have shown associations between dysfunctions in mitochondrial DNA (mtDNA), mtDNA copy number or mitochondrial-related nuclear genes and different cancer risks. However, these studies did not investigate causal inferences between mitochondrial dysfunction and cancers. We searched PubMed for studies in any language using the search terms “mitochondrion OR mitochondria OR mitochondrial dysfunction” AND “Mendelian randomization OR Mendelian randomisation” AND “cancer OR cancers”. Of the yielded 4 studies, three studies’ outcomes were COVID-19, dementia and type 2 diabetes, respectively. The other study was a meta-analysis study that presented heterogeneous estimates for the effect of mtDNA copy numbers on different cancer risks and suggested applying Mendelian randomization for unraveling the casual correlation of mtDNA copy number with cancer risk.
先前的研究表明,线粒体DNA(mtDNA)、mtDNA拷贝数或线粒体相关核基因的功能障碍与不同的癌症风险之间存在关联。然而,这些研究没有调查线粒体功能障碍与癌症之间的因果推断。我们使用检索词“线粒体或线粒体或线粒体功能障碍”和“孟德尔随机化”和“癌症或癌症”检索了PubMed的任何语言的研究。在产生的4项研究中,有3项研究的结局分别是COVID-19、痴呆和2型糖尿病。另一项研究是一项荟萃分析研究,该研究对mtDNA拷贝数对不同癌症风险的影响进行了异质性估计,并建议应用孟德尔随机化来揭示mtDNA拷贝数与癌症风险的偶然相关性。

Added value of this study
本研究的附加值

This data-driven study fills the gap by using Mendelian randomization to examine the potential causal relationship between mitochondrial dysfunction characterized by genetic predisposition in all mitochondrial-related genes and common cancer risks. Our findings provide evidence for the potential causal effect of mitochondrial dysfunction on breast, prostate and lung cancer, after sensitivity and colocalization analyses. In addition, we identified a shared putative causal gene, NSUN4, for both breast and prostate cancer. All associations underscore the importance of mitochondrial dysfunction in the pathogenesis of multiple cancer types.
这项数据驱动的研究通过使用孟德尔随机化来检查线粒体功能障碍(以所有线粒体相关基因的遗传易感性为特征)与常见癌症风险之间的潜在因果关系,从而填补了这一空白。我们的研究结果为线粒体功能障碍对乳腺癌、前列腺癌和肺癌的潜在因果效应提供了证据,经过敏感性和共定位分析。此外,我们还鉴定了乳腺癌和前列腺癌的共同推定致病基因NSUN4。所有关联都强调了线粒体功能障碍在多种癌症类型发病机制中的重要性。

Implications of all the available evidence
所有现有证据的意义

Our data-driven analyses support the increasing values in the application of publicly accessible datasets to inform public health. To date, our European population-based large-scale study and the available evidence, indicate that individuals with mitochondrial dysfunction have a higher risk of a certain type of cancer, and point to the necessity of objective measurement of mitochondrial function in epidemiologic studies. For the identified putative causal genes, it is feasible to be added to the genetic screening project for better cancer prevention. True causal effects of mitochondrial dysfunction on cancers might be more complex and need larger genetic datasets and sophisticated experimental studies to further confirm.
我们的数据驱动分析支持在应用可公开访问的数据集为公共卫生提供信息方面日益增长的价值。迄今为止,我们基于欧洲人群的大规模研究和现有证据表明,线粒体功能障碍患者患某种类型癌症的风险更高,并指出在流行病学研究中客观测量线粒体功能的必要性。对于已确定的推定致病基因,可以将其添加到基因筛查项目中,以更好地预防癌症。线粒体功能障碍对癌症的真正因果影响可能更加复杂,需要更大的遗传数据集和复杂的实验研究来进一步证实。

Introduction 介绍

Mitochondria are the essential organelles that regulate cellular energy production, metabolism, proliferation and apoptosis. An altered mitochondrial function is a well-known hallmark of cancer, which is commonly characterized by abnormal mitochondrial morphology, deficient mitochondrial copy numbers, aberrant energetic metabolism, accumulation of reactive oxygen species (ROS), imbalanced biogenesis and mitophagy. A mild mitochondrial dysfunction may enhance the amplification and invasion of cancer cells while a severe level of dysfunction may cause cell death to inhibit tumorigenesis. Thus, understanding the roles of mitochondrial dysfunction is essential for cancer research. Mitochondrial dysfunction is a complex cellular process that exhibits a spectrum of pathological conditions although there is no specific biomarker/s to define mitochondrial dysfunction., With the exception of the 37 critical bioenergetic genes encoded by the mitochondrion itself, the mitochondrial-related genome encompasses more than 1000 additional nuclear genes, and the genetic predisposition in those genes will potentially cause mitochondrial dysfunction. Many experimental and epidemiological studies have attempted to infer the causal relationship between mitochondrial dysfunction and cancer by exploring the selective mitochondrial DNA (mtDNA) and mitochondrial-related nuclear DNA mutations that affect mitochondrial function and are associated with the risk of specific cancer types., However, the results generated from those studies are inconsistent and one of the reasons is the methodologies used in these studies, which do not consider the effect of confounders to differentiate between cause and consequence. Therefore, a comprehensive analysis of all genes related to mitochondrial dysfunction in multiple cancer types by a robust method is required to determine whether mitochondrial dysfunction per se is a cause or consequence of cancer.
线粒体是调节细胞能量产生、代谢、增殖和凋亡的重要细胞器。线粒体功能改变是癌症的一个众所周知的标志,其通常特征是线粒体形态异常、线粒体拷贝数不足、能量代谢异常、活性氧 (ROS) 积累、生物发生和线粒体自噬失衡。 1 轻度线粒体功能障碍可能会增强癌细胞的扩增和侵袭,而严重的功能障碍可能会导致细胞死亡以抑制肿瘤发生。因此,了解线粒体功能障碍的作用对于癌症研究至关重要。线粒体功能障碍是一个复杂的细胞过程,尽管没有特定的生物标志物来定义线粒体功能障碍,但它表现出一系列病理状况。 2 3 除了线粒体本身编码的 37 个关键生物能量基因外,线粒体相关基因组包含 1000 多个额外的核基因,这些基因的遗传易感性可能会导致线粒体功能障碍。 4 许多实验和流行病学研究试图通过探索影响线粒体功能的选择性线粒体 DNA (mtDNA) 和线粒体相关核 DNA 突变来推断线粒体功能障碍与癌症之间的因果关系,这些突变与特定癌症类型的风险相关。 5 6 然而,这些研究产生的结果不一致,原因之一是这些研究中使用的方法,这些方法没有考虑混杂因素对区分原因和结果的影响。 因此,需要通过稳健的方法对多种癌症类型中与线粒体功能障碍相关的所有基因进行全面分析,以确定线粒体功能障碍本身是癌症的原因还是后果。

Mendelian randomization (MR) is a method that uses genetic variants as instrumental variables (IVs) to explore the potential causal association between lifetime exposure and outcome. In MR, the use of the conceptional random allocation of alleles avoids bias from unobserved confounders such as lifestyle and environmental factors and the problem with reverse causality. The two-sample MR allows for the assessment of the IVs-exposure association and IVs-outcome association generated from different populations. Genome-wide association studies (GWAS) exploit the genetic associations with traits based on single nucleotide polymorphisms (SNPs) and integration of the GWAS data with gene expression and methylation GWAS have allowed for the identification of expression or methylation quantitative trait loci (eQTL or mQTL)., A summary-data-based MR (SMR) has extended and developed the conception of MR that can utilize the independent GWAS summary statistics data and QTL data to prioritize potential causal genes from hits identified in GWAS. By applying this method followed by a heterogeneity independent instruments (HEIDI) test, the potential causal associations were distinguished from the widespread linkage disequilibrium (LD) in the genome.
孟德尔随机化 (MR) 是一种使用遗传变异作为工具变量 (IV) 来探索终生暴露与结果之间潜在因果关系的方法。在MR中,使用等位基因的概念随机分配可以避免来自未观察到的混杂因素的偏差,例如生活方式和环境因素以及反向因果关系问题。 7 双样本 MR 允许评估来自不同人群的 IVs 暴露关联和 IV s-结果关联。 8 全基因组关联研究 (GWAS) 利用基于单核苷酸多态性 (SNP) 的性状的遗传关联,并将 GWAS 数据与基因表达和甲基化 GWAS 整合,从而可以鉴定表达或甲基化数量性状位点(eQTL 或 mQTL)。 9 10 基于汇总数据的 MR (SMR) 扩展并发展了 MR 的概念,该概念可以利用独立的 GWAS 汇总统计数据和 QTL 数据来确定 GWAS 中确定的命中的潜在致病基因的优先级。 9 通过应用这种方法,然后进行异质性独立仪器 (HEIDI) 检验,将潜在的因果关联与基因组中广泛的连锁不平衡 (LD) 区分开来。

To our knowledge, there has been no MR study investigating the potential causal relationship between mitochondrial dysfunction and the risk of common types of cancer. Therefore, in this study, we aimed to investigate the causal relationship between mitochondrial dysfunction characterized by genetic predisposition in mitochondrial-related genes and multiple cancer types by the comprehensive two-sample MR analysis.
据我们所知,目前还没有MR研究调查线粒体功能障碍与常见类型癌症风险之间的潜在因果关系。因此,本研究旨在通过全面的双样本MR分析,探讨以线粒体相关基因遗传易感性为特征的线粒体功能障碍与多种癌症类型之间的因果关系。

Methods 方法

This study was conducted following the reporting guideline of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE, Supplementary STROBE-MR checklist table).
本研究是按照加强流行病学观察性研究报告的报告指南(STROBE,补充 STROBE-MR 清单表)进行。 11

Study design 研究设计

Fig. 1 summarizes the design of the present study and the workflow of the selection of genetic variants and analytical methods. To determine the mitochondrial dysfunction characterized by the genetic predisposition in the mitochondrial-related genome constituting from both mitochondrion and nuclear, we extracted the inventory of 1136 known mitochondrial-related genes from the human MitoCarta3.0 database.
图1总结了本研究的设计以及遗传变异选择和分析方法的工作流程。为了确定线粒体功能障碍的特征,以线粒体和核构成的线粒体相关基因组的遗传易感性为特征,我们从人类 MitoCarta3.0 数据库中提取了 1136 个已知线粒体相关基因的库存。 4

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Flowchart of the analyses performed.
所执行分析的流程图。

To generate eQTL instruments for mitochondrial genes, genetic variants located within 1000 kb on either side of the coding sequence (in cis) that are robustly associated with gene expression were extracted using eQTLs summary statistics obtained from the eQTLGen Consortium (https://www.eqtlgen.org/cis-eqtls.html). The eQTLGen Consortium contains information on 10,317 trait-associated single nucleotide polymorphisms (SNPs) from 31,684 individuals. However, the eQTLGen did not include variants associated with the expression level of genes located on the X and Y chromosomes and mtDNA. From cis-eQTL, 662,968 SNPs associated with the expression of 1013 mitochondrial-related transcripts were selected. MR cis-mQTL instruments for genetic variants robustly associated with mitochondrial gene methylation were extracted using summary data from a meta-analysis of two cohorts (n = 1980). In total, 931,304 SNPs were selected corresponding to 2550 mitochondrial-related DNA methylation CpG sites. MR cis-pQTL instruments for genetic variants associated with the expression of mitochondrial-related proteins were selected from five proteome datasets,, , , , and 23 SNPs that were robustly associated with 23 mitochondrial-related protein expressions were selected. All SNPs included in the initial analysis had at least a suggestive Psnp-mitodys <5 × 10−8.
为了生成线粒体基因的 eQTL 工具,使用从 eQTLGen 联盟 (https://www.eqtlgen.org/cis-eqtls.html) 获得的 eQTL 汇总统计提取位于编码序列两侧(顺式)两侧 1000 kb 以内且与基因表达密切相关的遗传变异。eQTLGen 联盟包含来自 31,684 个个体的 10,317 个性状相关单核苷酸多态性 (SNP) 的信息。 12 然而,eQTLGen不包括与位于X和Y染色体和mtDNA上的基因表达水平相关的变异。从cis-eQTL中,筛选出662,968个与1013个线粒体相关转录本表达相关的SNP。使用来自两个队列 (n = 1980) 的荟萃分析的汇总数据提取与线粒体基因甲基化密切相关的遗传变异的 MR cis-mQTL 工具。 10 总共选择了 931,304 个 SNP,对应于 2550 个线粒体相关 DNA 甲基化 CpG 位点。从5个蛋白质组数据集中选取与线粒体相关蛋白表达相关的遗传变异的MR顺式-pQTL仪器,选择13、14、15、16、17和23个SNPs,这些SNPs与23个线粒体相关蛋白表达密切相关。初始分析中包含的所有 SNP 都至少具有提示性 snp-mitodys P <5 × 10 −8

GWAS summary statistics for cancer outcomes were obtained from publicly available databases. A total of 18 types of cancers were included. The details of all QTL and GWAS datasets for this study are presented in Supplementary Table S1 and Supplementary methods.
GWAS癌症结局的汇总统计数据来自公开可用的数据库。共纳入18种癌症。本研究的所有QTL和GWAS数据集的详细信息在补充表S1和补充方法中列出。

Statistical analysis 统计分析

The main analyses involved three stages: primary SMR analyses, sensitivity analyses and colocalization analyses.
主要分析涉及三个阶段:初级SMR分析、敏感性分析和共定位分析。

Mendelian randomization requires meeting three core assumptions (Supplementary methods). As an extension of the MR concept, SMR was developed to estimate the pleiotropic association between genetically determined traits (e.g., gene expression, DNA methylation, or protein abundance as exposure) and complex traits of interest (e.g., disease phenotype as outcome). To meet MR assumptions in our study, the causal association was calculated as:
孟德尔随机化需要满足三个核心假设(补充方法)。作为 MR 概念的扩展,开发了 SMR 来估计遗传决定性状(例如,基因表达、DNA 甲基化或作为暴露的蛋白质丰度)与感兴趣的复杂性状(例如,疾病表型作为结果)之间的多效性关联。 9 为了满足我们研究中的 MR 假设,因果关联计算如下:

βmitodyscancer=β