Mendelian randomization for causal inference accounting for pleiotropy and sample structure using genome-wide summary statistics

Xianghong Hu, Jia Zhao, Zhixiang Lin, Yang Wang, Heng Peng, Hongyu Zhao*, Xiang Wan*, Can Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

34 Citations (Scopus)


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.

Original languageEnglish
Article numbere2106858119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number28
Early online date5 Jul 2022
Publication statusPublished - 12 Jul 2022

Scopus Subject Areas

  • General

User-Defined Keywords

  • causal inference
  • Mendelian randomization
  • pleiotropy
  • sample structure
  • selection bias


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