ArticleProceedings of the National Academy of Sciences of the United States of America2022
Mendelian randomization for causal inference accounting for pleiotropy and sample structure using genome-wide summary statistics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06666647 (Ambulance and Helicopter Response Times in Danish Emergency Medical Services), which is not on this map. Cited by 78 papers, 4 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Ambulance and Helicopter Response Times in Danish Emergency Medical Services: Protocol for an Epidemiological Study. The AHRTEMIS Study
Who cites it
78 citing papers in PubMed, 4 syntheses or guidelines pooled it.
- Causality and potential drug targets for hyperandrogenism and anovulation-related infertility: two-sample Mendelian randomization and colocalization analyses.Journal of ovarian research · 2025Pooled it
- Summarizing attributable factors and evaluating risk of bias of Mendelian randomization studies for Alzheimer's dementia and cognitive status: a systematic review and meta-analysis.Systematic reviews · 2025Pooled it
- No causal relationship between thyroid function and Parkinson's disease: A bidirectional Mendelian randomization study.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Pooled it
- Univariable and multivariable mendelian randomization study revealed the modifiable risk factors of urolithiasis.PloS one · 2023Pooled it
- A flexible framework for robust and efficient Mendelian randomization with debiasing.Briefings in bioinformatics · 2026Article
- The Omnicausal Model Reveals the Highly Polyfactorial Nature of Complex Diseases.Genetic epidemiology · 2026Article
- Association between antidepressant use and the risk of type 2 diabetes: a multi-stage Mendelian randomization study.European archives of psychiatry and clinical neuroscience · 2026Article
- Shared genetic architecture and neurobiological pathways of problematic alcohol use and anxiety disorders.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Recalibrating Mendelian randomization under winner's curse, sample structure and polygenicity.medRxiv : the preprint server for health sciences · 2026Article
- METEOR: a data-adaptive Mendelian randomization method for powerful detection of shared and specific exposures underlying multiple outcomes.Briefings in bioinformatics · 2026Article
- The genetic architecture of cortical similarity networks.Nature communications · 2026Article
- Causal link between maternal PCOS and fetal/neonatal hemorrhagic and hematological disorders: A 2-sample MR study.Medicine · 2026Article
- MR2G: A novel framework for causal network inference using GWAS summary data.PLoS genetics · 2026Article
- Genetic and Proteomic Investigation of the Smoking-Parkinson's Disease Association.medRxiv : the preprint server for health sciences · 2026Article
- Neutrophil extracellular traps-associated candidate genes in IgA vasculitis: an exploratory multi-omics analysis integrating transcriptomics and Mendelian randomization.Pediatric rheumatology online journal · 2026Article
- Winner's Curse Free Robust Mendelian Randomization with Summary Data.Journal of the American Statistical Association · 2026Article
- Crotonylation and the Risk of Head and Neck Cancer: Insights from a Two-Sample Mendelian Randomization Study.International dental journal · 2026Article
- Chronic Kidney Disease as a Risk Factor for Age-Related Macular Degeneration: A Prospective Cohort and Mendelian Randomization Analyses.Ophthalmology science · 2026Article
- Gallbladder disease and colorectal cancer: a two-sample bidirectional Mendelian randomization study.Discover oncology · 2026Article
- Exploring the potential causal role of IgG N-glycosylation in urological cancers: a two-sample Mendelian randomization study using European ancestry datasets.Archives of medical science : AMS · 2026Article
18 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Mendelian randomization (MR) is a valuable tool for inferring causal relationships among a wide range of traits using summary statistics from genome-wide association studies (GWASs). Existing summary-level MR methods often rely on strong assumptions, resulting in many false-positive findings. To relax MR assumptions, ongoing research has been primarily focused on accounting for confounding due to pleiotropy. Here, we show that sample structure is another major confounding factor, including population stratification, cryptic relatedness, and sample overlap. We propose a unified MR approach, MR-APSS, which 1) accounts for pleiotropy and sample structure simultaneously by leveraging genome-wide information; and 2) allows the inclusion of more genetic variants with moderate effects as instrument variables (IVs) to improve statistical power without inflating type I errors. We first evaluated MR-APSS using comprehensive simulations and negative controls and then applied MR-APSS to study the causal relationships among a collection of diverse complex traits. The results suggest that MR-APSS can better identify plausible causal relationships with high reliability. In particular, MR-APSS can perform well for highly polygenic traits, where the IV strengths tend to be relatively weak and existing summary-level MR methods for causal inference are vulnerable to confounding effects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.