Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score

Qingyuan Zhao, Jingshu Wang, Gibran Hemani, Jack Bowden, Dylan S. Small

Research output: Contribution to journalArticle (Academic Journal)peer-review

326 Citations (Scopus)
1516 Downloads (Pure)


Mendelian randomization (MR) is a method of exploiting genetic variation to unbiasedly estimate a causal effect in presence of unmeasured confounding. MR is being widely used in epidemiology and other related areas of population science. In this paper, we study statistical inference in the increasingly popular two-sample summary-data MR design. We show a linear model for the observed associations approximately holds in a wide variety of settings when all the genetic variants satisfy the exclusion restriction assumption, or in genetic terms, when there is no pleiotropy. In this scenario, we derive a maximum profile likelihood estimator with provable consistency and asymptotic normality. However, through analyzing real datasets, we find strong evidence of both systematic and idiosyncratic pleiotropy in MR, echoing some recent discoveries in statistical genetics. We model the systematic pleiotropy by a random effects model, where no genetic variant satisfies the exclusion restriction condition exactly. In this case we propose a consistent and asymptotically normal estimator by adjusting the profile score. We then tackle the idiosyncratic pleiotropy by robustifying the adjusted profile score. We demonstrate the robustness and efficiency of the proposed methods using several simulated and real datasets.
Original languageEnglish
JournalAnnals of Statistics
Issue number3
Publication statusPublished - 17 Jul 2020


  • stat.AP
  • math.ST
  • stat.TH
  • 65J05, 46N60, 62F35


Dive into the research topics of 'Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score'. Together they form a unique fingerprint.

Cite this