Mendelian-randomization

Mendelian randomization (MR)

一行要約

Mendelian randomization は germline genetic variant (主に SNP) を instrumental variable (IV) として用い、観察研究の交絡を回避して exposure → outcome の因果関係を推定する遺伝疫学手法。Random Mendel allocation (受精時の random allele 分配) を「natural experiment」と捉える。腫瘍領域では smoking → lung cancer, BMI → cancer risk, 炎症マーカー (CRP / IL-6) → cancer 因果性, druggable target (PCSK9, IL-6R) の validation に応用。RCT 設計困難な exposure (life-long inflammatory state, lipid profile) で causal evidence を提供。

原理

3 つの IV 仮定

1. Relevance: SNP が exposure と強く関連 (F-statistic > 10)
2. Independence: SNP が confounder と独立 (population stratification 補正)
3. Exclusion restriction: SNP は exposure 経由でしか outcome に影響しない (no horizontal pleiotropy)

解析法

手法	用途
Inverse-variance weighted (IVW)	標準推定量 (no pleiotropy 仮定)
MR-Egger	directional pleiotropy 補正 + intercept 検定
Weighted median	50% 以上の SNP が valid なら robust
MR-PRESSO	outlier SNP 検出 + 補正
Two-sample MR	exposure と outcome の GWAS が異なる cohort
Multivariable MR	複数 exposure 同時推定
Drug-target MR	drug target 周辺 cis-eQTL を IV、薬物効果の予測

主要エビデンス / 適用領域

• Smoking → lung cancer: nicotine receptor (CHRNA5) SNP IV で smoking の lung cancer 因果性を強化, Bradford-Hill 補完
• BMI → cancer: 多 cancer 種 BMI の causal role 推定 (renal / pancreatic / colorectal)
• IL-6 / CRP → cancer: IL-6R SNP IV で IL-6 axis の cancer-causal role を tocilizumab 様 effect として推定
• Lipid → cancer: HDL/LDL/triglyceride の MR で cancer 因果性 (mostly null)
• Drug target validation: PCSK9 cis-eQTL → cardiovascular outcome MR で alirocumab 効果予測。同様に oncology drug target (e.g. IL-1β → CANTOS post-hoc) で MR confirmation

適用分野と限界

• 強み: RCT 困難な exposure に causal evidence、一生涯 exposure の cumulative effect、drug target validation で開発前提とできる
• 限界: pleiotropy (SNP が複数経路に作用) 完全排除困難、weak instrument bias、population overlap (sample 1 と sample 2 重複) で type-1 error 増大、effect estimate は life-long average で acute effect とは異なる、causal inference は RCT より gradient lower

Open Questions

• Polygenic risk score を IV とする power 向上
• Single-cell MR: cell-type-specific eQTL を IV
• Cross-ancestry MR: 多民族 GWAS で generalizability
• Drug repurposing: large-scale drug-target MR で oncology candidate identification

関連エンティティ

• 補完手法: Real-world-data-analysis / NGS-panel / Machine-learning-AI
• 関連概念: Tumor-promoting-inflammation / Microbiome-cancer-immunity

関連論文

直近 30 件のみ表示中 (関連 47 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Eguren-Santamaria et al. ClinCancerRes 2020 — PD-1pd-L1 blockers in NSCLC brain metastases challenging paradigms and clinical practice
• Bongiovanni et al. FrontImmunol 2021 — Immune checkpoint inhibitors with or without bone-targeted therapy in NSCLC patients with bone metastases and
• Dewhirst et al. NatRevCancer 2017 — Transport of drugs from blood vessels to tumour tissue

Basic-Extracellular vesicles

• Thery et al. JExtracellVesicles 2018 — Minimal information for studies of extracellular vesicles 2018 (MISEV2018) a position statement of the international

Basic-Immunotherapy

• Nissim et al. Cell 2017 — Synthetic RNA-based immunomodulatory gene circuits for cancer immunotherapy
• Thorsson et al. Immunity 2018 — The immune landscape of cancer

Basic-Liquid-biopsy

• Heeke et al. CancerCell 2024 — Tumor-and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes

Basic-Oncogene and genetics

• janes et al. Cell 2018 — Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor
• Hahn et al. Cell 2021 — An expanded universe of cancer targets
• Roerink et al. Nature 2018 — Intra-tumour diversification in colorectal cancer at the single-cell level
• Wu et al. Nature 2019 — Circular ecDNA promotes accessible chromatin and high oncogene expression
• Hung et al. Nature 2021 — ecDNA hubs drive cooperative intermolecular oncogene expression

Basic-Others

• Zhu et al. CancerMed 2026 — Harnessing gut microbiota to enhance immunotherapy in NSCLC from mechanisms to translational applications
• Jia et al. CellMetab 2026 — Plasma proteomic signature of frailty in 50,506 adults
• Sun et al. Nature 2018 — Genomic atlas of the human plasma proteome
• Western et al. SciTranslMed 2026 — Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease
• Lin et al. Science 2026 — Antifibrotic drug finerenone restores fertility in premature ovarian insufficiency
• Davalos et al. TrendsCancer 2026 — How DNA methylation predicts response to cancer therapies

Clinical-Epidemiology

• Shi et al. Cell 2026 — Accelerating discovery of cancer causes for prevention in the era of rising early-onset cancers
• Global Burden of Disease 2019 Cancer Collaboration et al. JAMAOncol 2022 — Cancer incidence, moratlity, years of life lost, years live with disability, and disability-adjusted life years for 2…
• GBD et al. Lancet 2024 — Global fertility in 204 countries and territories, 1950-2021, with forecasts to 2100 a comprehensive demographic

Clinical-Methodology

• Chatton et al. SciRep 2020 — G-computation, propensity score-based methods, and targeted maximum likelihood estimator for causal inference with

Clinical-NEC

• Alvarez et al. NatGenet 2018 — A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine

Clinical-NSCLC-Driver negative

• Ramalingam et al. JClinOncol 2019 — Pemetrexed, bevacizumab, or the combination as maintenance therapy for advanced nonsquamous non-small-cell lung cancer
• Provencio et al. JClinOncol 2022 — Overall survival and biomarker analysis of neoadjuvant nivolumab plus chemotherapy in operable stage IIIA
• Wang et al. LungCancer 2019 — Erratum to the metastatic site does not influence PD-L1 expression in advanced non-small cell lung carcinoma

Clinical-NSCLC-EGFR

• Magnuson et al. JClinOncol 2017 — Management of brain metastases in tyrosine kinase inhibitor-naive epidermal growth factor receptor-mutant

Clinical-NSCLC-ROS1

• Yun et al. ClinCancerRes 2020 — Repotrectinib exhibits potent antitumor activity in treatment-naive and solvent-front-mutant ROS1-rearranged non-small
• Drilon et al. LancetOncol 2020 — Entrectinib in ROS1 fusion-positive non-small-cell lung cancer integrated analysis of three phase 1-2 trials

Clinical-irAE

• Varricchi et al. ESMOOpen 2017 — Cardiotoxicity of immune checkpoint inhibitors