Human Genetics

, Volume 134, Issue 7, pp 761–773

A cautionary note on the impact of protocol changes for genome-wide association SNP × SNP interaction studies: an example on ankylosing spondylitis

  • Kyrylo Bessonov
  • Elena S. Gusareva
  • Kristel Van Steen
Original Investigation

DOI: 10.1007/s00439-015-1560-7

Cite this article as:
Bessonov, K., Gusareva, E.S. & Van Steen, K. Hum Genet (2015) 134: 761. doi:10.1007/s00439-015-1560-7


Genome-wide association interaction (GWAI) studies have increased in popularity. Yet to date, no standard protocol exists. In practice, any GWAI workflow involves making choices about quality control strategy, SNP filtering, linkage disequilibrium (LD) pruning, analytic tool to model or to test for genetic interactions. Each of these can have an impact on the final epistasis findings and may affect their reproducibility in follow-up analyses. Choosing an analytic tool is not straightforward, as different tools exist and current understanding about their performance is based on often very particular simulation settings. In the present study, we wish to create awareness for the impact of (minor) changes in a GWAI analysis protocol can have on final epistasis findings. In particular, we investigate the influence of marker selection and marker prioritization strategies, LD pruning and the choice of epistasis detection analytics on study results, giving rise to 8 GWAI protocols. Discussions are made in the context of the ankylosing spondylitis (AS) data obtained via the Wellcome Trust Case Control Consortium (WTCCC2). As expected, the largest impact on AS epistasis findings is caused by the choice of marker selection criterion, followed by marker coding and LD pruning. In MB-MDR, co-dominant coding of main effects is more robust to the effects of LD pruning than additive coding. We were able to reproduce previously reported epistasis involvement of HLA-B and ERAP1 in AS pathology. In addition, our results suggest involvement of MAGI3 and PARK2, responsible for cell adhesion and cellular trafficking. Gene ontology biological function enrichment analysis across the 8 considered GWAI protocols also suggested that AS could be associated to the central nervous system malfunctions, specifically, in nerve impulse propagation and in neurotransmitters metabolic processes.

Supplementary material

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Supplementary material 1 (PDF 211 kb)
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Supplementary material 2 (PDF 204 kb)
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Supplementary material 3 (XLSX 7062 kb)
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Supplementary material 4 (XLS 296 kb)
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Supplementary material 6 (XLS 149 kb)

Funding information

Funder NameGrant NumberFunding Note
Fonds de la Recherche Scientifique (FNRS)
  • n° 2.4609.11

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Kyrylo Bessonov
    • 1
    • 2
  • Elena S. Gusareva
    • 1
    • 2
  • Kristel Van Steen
    • 1
    • 2
  1. 1.Systems and Modeling Unit, Montefiore InstituteUniversity of LiègeLiègeBelgium
  2. 2.Systems Biology and Chemical Biology, GIGA-R, University of LiègeLiègeBelgium

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