University of Leicester
Browse
s41467-022-28119-9.pdf (3.5 MB)

A robust method for collider bias correction in conditional genome-wide association studies

Download (3.5 MB)
journal contribution
posted on 2022-05-18, 10:38 authored by O. Mahmoud, F. Dudbridge, G. Davey Smith, M. Munafo, K. Tilling
Estimated genetic associations with prognosis, or conditional on a phenotype (e.g. disease incidence), may be affected by collider bias, whereby conditioning on the phenotype induces associations between causes of the phenotype and prognosis. We propose a method, 'Slope-Hunter', that uses model-based clustering to identify and utilise the class of variants only affecting the phenotype to estimate the adjustment factor, assuming this class explains more variation in the phenotype than any other variant classes. Simulation studies show that our approach eliminates the bias and outperforms alternatives even in the presence of genetic correlation. In a study of fasting blood insulin levels (FI) conditional on body mass index, we eliminate paradoxical associations of the underweight loci: COBLLI; PPARG with increased FI, and reveal an association for the locus rs1421085 (FTO). In an analysis of a case-only study for breast cancer mortality, a single region remains associated with more pronounced results.

Funding

F.D. was supported by the Medical Research Council (MRC) [grant number: MR/S037055/1]. G.D.S., M.M. and K.T. work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol [MC_UU_00011/1], [MC_UU_00011/7] and [MC_UU_00011/3], respectively.

History

Citation

Nat Commun 13, 619 (2022)

Author affiliation

Department of Health Sciences

Version

  • VoR (Version of Record)

Published in

Nature communications

Volume

13

Publisher

Nature Research

issn

2041-1723

eissn

2041-1723

Acceptance date

2022-01-04

Copyright date

2022

Available date

2022-05-18

Language

eng

Usage metrics

    University of Leicester Publications

    Categories

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC