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Massive false-positive gene–gene interactions by Rothman’s additive model
  1. Kwangwoo Kim
  1. Department of Biology, Kyung Hee University, Seoul 02447, South Korea
  1. Correspondence to Professor Kwangwoo Kim, Department of Biology, Kyung Hee University, Seoul 02447, South Korea; kkim{at}khu.ac.kr

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Rothman’s additive interaction model based on additivity of the relative risks of two disease-risk factors has frequently been used to investigate gene–gene interactions for various traits, especially for rheumatic diseases compared with other diseases (online supplementary text). For example, a recent paper by Diaz-Gallo et al 1 reported significant additive interactions between the HLA-DRB1 shared-epitope allele and numerous non-HLA rheumatoid arthritis (RA) risk variants (eg, PTPN22 variants) in anti-citrullinated protein antibody–positive (ACPA-positive) RA.

Supplementary data

[annrheumdis-2018-214297-supp1.pdf]

This study investigated the validity of the additive interaction model in assessing gene–gene interactions. Genome-wide association study (GWAS) datasets including 1000 cases and 1000 controls were simulated 100 times based on an actual GWAS dataset from 2849 WTCCC2 controls (1958_British_Birth) to have European genomic features and a single variant with OR≈5, 3, 2, 1.5, 1.2 or 1 in a dominant genetic model (used in a typical additive interaction analysis). The simulated dataset is expected to have no true disease-risk effects of variants (except for an OR-simulated variant) and no true biological interaction effects between any variants on risk of a fake disease. Using the simulated datasets, all possible interactions between an OR-simulated variant and other variants in different chromosomes …

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