Genetic Epidemiology

Constrained instruments and their application to Mendelian randomization with pleiotropy

Early View

  • Author(s): Lai Jiang, Karim Oualkacha, Vanessa Didelez, Antonio Ciampi, Pedro Rosa‐Neto, Andrea L. Benedet, Sulantha Mathotaarachchi, John Brent Richards, Celia M. T. Greenwood
  • Article first published online: 12 Jan 2019
  • DOI: 10.1002/gepi.22184
  • Read on Online Library
  • Subscribe to Journal

Abstract In Mendelian randomization (MR), inference about causal relationship between a phenotype of interest and a response or disease outcome can be obtained by constructing instrumental variables from genetic variants. However, MR inference requires three assumptions, one of which is that the genetic variants only influence the outcome through phenotype of interest. Pleiotropy, that is, the situation in which some genetic variants affect more than one phenotype, can invalidate these genetic variants for use as instrumental variables; thus a naive analysis will give biased estimates of the causal relation. Here, we present new methods (constrained instrumental variable [CIV] methods) to construct valid instrumental variables and perform adjusted causal effect estimation when pleiotropy exists and when the pleiotropic phenotypes are available. We demonstrate that a smoothed version of CIV performs approximate selection of genetic variants that are valid instruments, and provides unbiased estimates of the causal effects. We provide details on a number of existing methods, together with a comparison of their performance in a large series of simulations. CIV performs robustly across different pleiotropic violations of the MR assumptions. We also analyzed the data from the Alzheimer’s disease (AD) neuroimaging initiative (ADNI; Mueller et al., 2005. Alzheimer's Dementia, 11(1), 55–66) to disentangle causal relationships of several biomarkers with AD progression.

Related Topics

Related Publications

Related Content

Site Footer

Address:

This website is provided by John Wiley & Sons Limited, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ (Company No: 00641132, VAT No: 376766987)

Published features on StatisticsViews.com are checked for statistical accuracy by a panel from the European Network for Business and Industrial Statistics (ENBIS)   to whom Wiley and StatisticsViews.com express their gratitude. This panel are: Ron Kenett, David Steinberg, Shirley Coleman, Irena Ograjenšek, Fabrizio Ruggeri, Rainer Göb, Philippe Castagliola, Xavier Tort-Martorell, Bart De Ketelaere, Antonio Pievatolo, Martina Vandebroek, Lance Mitchell, Gilbert Saporta, Helmut Waldl and Stelios Psarakis.