GENIUS-MAWII: for Robust Mendelian Randomization with Many Weak Invalid Instruments

Overview

Journal J R Stat Soc Series B Stat Methodol

Date 2024 Sep 16

PMID 39279912

Authors

Ting Ye

Zhonghua Liu

Baoluo Sun

Eric Tchetgen Tchetgen

Affiliations

Soon will be listed here.

Abstract

Mendelian randomization (MR) addresses causal questions using genetic variants as instrumental variables. We propose a new MR method, G-Estimation under No Interaction with Unmeasured Selection (GENIUS)-MAny Weak Invalid IV, which simultaneously addresses the 2 salient challenges in MR: many weak instruments and widespread horizontal pleiotropy. Similar to MR-GENIUS, we use heteroscedasticity of the exposure to identify the treatment effect. We derive influence functions of the treatment effect, and then we construct a continuous updating estimator and establish its asymptotic properties under a many weak invalid instruments asymptotic regime by developing novel semiparametric theory. We also provide a measure of weak identification, an overidentification test, and a graphical diagnostic tool.

Citing Articles

A Review of Mendelian Randomization: Assumptions, Methods, and Application to Obesity-Related Diseases.

Lee S, Lee W J Obes Metab Syndr. 2025; 34(1):14-26.

PMID: 39809435 PMC: 11799604. DOI: 10.7570/jomes24031.

Best-subset instrumental variable selection method using mixed integer optimization with applications to health-related quality of life and education-wage analyses.

Qasim M, Mansson K, Balakrishnan N Res Sq. 2024; .

PMID: 39678322 PMC: 11643330. DOI: 10.21203/rs.3.rs-5550004/v1.

References

Burgess S, Butterworth A, Thompson S . Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013; 37(7):658-65. PMC: 4377079. DOI: 10.1002/gepi.21758. View

Bowden J, Davey Smith G, Haycock P, Burgess S . Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016; 40(4):304-14. PMC: 4849733. DOI: 10.1002/gepi.21965. View

Davey Smith G, Ebrahim S . Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol. 2004; 33(1):30-42. DOI: 10.1093/ije/dyh132. View

Lyall D, Celis-Morales C, Ward J, Iliodromiti S, Anderson J, Gill J . Association of Body Mass Index With Cardiometabolic Disease in the UK Biobank: A Mendelian Randomization Study. JAMA Cardiol. 2017; 2(8):882-889. PMC: 5710596. DOI: 10.1001/jamacardio.2016.5804. View

Zhao Q, Chen Y, Wang J, Small D . Powerful three-sample genome-wide design and robust statistical inference in summary-data Mendelian randomization. Int J Epidemiol. 2019; 48(5):1478-1492. DOI: 10.1093/ije/dyz142. View

Hartwig F, Davey Smith G, Bowden J . Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017; 46(6):1985-1998. PMC: 5837715. DOI: 10.1093/ije/dyx102. View

Liu Z, Ye T, Sun B, Schooling M, Tchetgen Tchetgen E . Mendelian randomization mixed-scale treatment effect robust identification and estimation for causal inference. Biometrics. 2022; 79(3):2208-2219. DOI: 10.1111/biom.13735. View

Wang S, Kang H . Weak-instrument robust tests in two-sample summary-data Mendelian randomization. Biometrics. 2021; 78(4):1699-1713. DOI: 10.1111/biom.13524. View

Parkes M, Cortes A, van Heel D, Brown M . Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet. 2013; 14(9):661-73. DOI: 10.1038/nrg3502. View

10.

Qi G, Chatterjee N . Mendelian randomization analysis using mixture models for robust and efficient estimation of causal effects. Nat Commun. 2019; 10(1):1941. PMC: 6486646. DOI: 10.1038/s41467-019-09432-2. View

11.

Morrison J, Knoblauch N, Marcus J, Stephens M, He X . Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics. Nat Genet. 2020; 52(7):740-747. PMC: 7343608. DOI: 10.1038/s41588-020-0631-4. View

12.

Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J . UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015; 12(3):e1001779. PMC: 4380465. DOI: 10.1371/journal.pmed.1001779. View

13.

Wang J, Zhao Q, Bowden J, Hemani G, Davey Smith G, Small D . Causal inference for heritable phenotypic risk factors using heterogeneous genetic instruments. PLoS Genet. 2021; 17(6):e1009575. PMC: 8301661. DOI: 10.1371/journal.pgen.1009575. View

14.

Sivakumaran S, Agakov F, Theodoratou E, Prendergast J, Zgaga L, Manolio T . Abundant pleiotropy in human complex diseases and traits. Am J Hum Genet. 2011; 89(5):607-18. PMC: 3213397. DOI: 10.1016/j.ajhg.2011.10.004. View

15.

Stephens A, Tchetgen Tchetgen E, de Gruttola V . Locally efficient estimation of marginal treatment effects when outcomes are correlated: is the prize worth the chase?. Int J Biostat. 2014; 10(1):59-75. PMC: 4142698. DOI: 10.1515/ijb-2013-0031. View

16.

Pare G, Cook N, Ridker P, Chasman D . On the use of variance per genotype as a tool to identify quantitative trait interaction effects: a report from the Women's Genome Health Study. PLoS Genet. 2010; 6(6):e1000981. PMC: 2887471. DOI: 10.1371/journal.pgen.1000981. View

17.

Grassmann F, Kiel C, Zimmermann M, Gorski M, Grassmann V, Stark K . Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits. Genome Med. 2017; 9(1):29. PMC: 5368911. DOI: 10.1186/s13073-017-0418-0. View

18.

Wang X, Jiang Y, Zhang N, Small D . Sensitivity analysis and power for instrumental variable studies. Biometrics. 2018; 74(4):1150-1160. DOI: 10.1111/biom.12873. View

19.

Burgess S, Timpson N, Ebrahim S, Davey Smith G . Mendelian randomization: where are we now and where are we going?. Int J Epidemiol. 2015; 44(2):379-88. DOI: 10.1093/ije/dyv108. View

20.

Windmeijer F, Farbmacher H, Davies N, Davey Smith G . On the Use of the Lasso for Instrumental Variables Estimation with Some Invalid Instruments. J Am Stat Assoc. 2019; 114(527):1339-1350. PMC: 6817329. DOI: 10.1080/01621459.2018.1498346. View