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Adjusting for collider bias in genetic association studies using instrumental variable methods

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journal contribution
posted on 2022-07-01, 14:51 authored by Siyang Cai, April Hartley, Osama Mahmoud, Kate Tilling, Frank Dudbridge
Genome-wide association studies have provided many genetic markers that can be used as instrumental variables to adjust for confounding in epidemiological studies. Recently, the principle has been applied to other forms of bias in observational studies, especially collider bias that arises when conditioning or stratifying on a variable that is associated with the outcome of interest. An important case is in studies of disease progression and survival. Here, we clarify the links between the genetic instrumental variable methods proposed for this problem and the established methods of Mendelian randomisation developed to account for confounding. We highlight the critical importance of weak instrument bias in this context and describe a corrected weighted least-squares procedure as a simple approach to reduce this bias. We illustrate the range of available methods on two data examples. The first, waist-hip ratio adjusted for body-mass index, entails statistical adjustment for a quantitative trait. The second, smoking cessation, is a stratified analysis conditional on having initiated smoking. In both cases, we find little effect of collider bias on the primary association results, but this may propagate into more substantial effects on further analyses such as polygenic risk scoring and Mendelian randomisation.

Funding

Siyang Cai and Frank Dudbridge are supported by the MRC (MR/S037055/1). Kate Tilling and April Hartley are part of the MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, which is supported by the MRC (MC_UU_00011/1 and MC_UU_00011/3).

History

Citation

Cai, S., Hartley, A., Mahmoud, O., Tilling, K., & Dudbridge, F. (2022). Adjusting for collider bias in genetic association studies using instrumental variable methods. Genetic Epidemiology, 1– 14. https://doi.org/10.1002/gepi.22455

Author affiliation

Department of Health Sciences

Version

  • VoR (Version of Record)

Published in

GENETIC EPIDEMIOLOGY

Pagination

1-14

Publisher

WILEY

issn

0741-0395

eissn

1098-2272

Acceptance date

2022-04-20

Copyright date

2022

Available date

2022-07-01

Language

English