Genetic Epidemiology

On the adjustment for covariates in genetic association analysis: a novel, simple principle to infer direct causal effects

Journal Article

  • Author(s): Stijn Vansteelandt, Sylvie Goetgeluk, Sharon Lutz, Irwin Waldman, Helen Lyon, Eric E. Schadt, Scott T. Weiss, Christoph Lange
  • Article first published online: 13 Feb 2009
  • DOI: 10.1002/gepi.20393
  • Read on Online Library
  • Subscribe to Journal


In genetic association studies, different complex phenotypes are often associated with the same marker. Such associations can be indicative of pleiotropy (i.e. common genetic causes), of indirect genetic effects via one of these phenotypes, or can be solely attributable to non‐genetic/environmental links between the traits. To identify the phenotypes with the inducing genetic association, statistical methodology is needed that is able to distinguish between the different causes of the genetic associations. Here, we propose a simple, general adjustment principle that can be incorporated into many standard genetic association tests which are then able to infer whether an SNP has a direct biological influence on a given trait other than through the SNP's influence on another correlated phenotype. Using simulation studies, we show that, in the presence of a non‐marker related link between phenotypes, standard association tests without the proposed adjustment can be biased. In contrast to that, the proposed methodology remains unbiased. Its achieved power levels are identical to those of standard adjustment methods, making the adjustment principle universally applicable in genetic association studies. The principle is illustrated by an application to three genome‐wide association analyses. Genet. Epidemiol. 33:394–405, 2009. © 2009 Wiley‐Liss, Inc.

Related Topics

Related Publications

Related Content

Site Footer


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 are checked for statistical accuracy by a panel from the European Network for Business and Industrial Statistics (ENBIS)   to whom Wiley and 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.