The challenge of detecting genotype-by-methylation interaction: GAW20

de Andrade, Mariza; Warwick Daw, E.; Kraja, Aldi T.; Fisher, Virginia; Wang, Lan; Hu, Ke; Li, Jing; Romanescu, Razvan; Veenstra, Jenna; Sun, Rui; Weng, Haoyi; Zhou, Wenda

GAW20 working group 5 brought together researchers who contributed 7 papers with the aim of evaluating methods to detect genetic by epigenetic interactions. GAW20 distributed real data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, including single-nucleotide polymorphism (SNP) markers, methylation (cytosine-phosphate-guanine [CpG]) markers, and phenotype information on up to 995 individuals. In addition, a simulated data set based on the real data was provided.

The 7 contributed papers analyzed these data sets with a number of different statistical methods, including generalized linear mixed models, mediation analysis, machine learning, W-test, and sparsity-inducing regularized regression. These methods generally appeared to perform well. Several papers confirmed a number of causative SNPs in either the large number of simulation sets or the real data on chromosome 11. Findings were also reported for different SNPs, CpG sites, and SNP–CpG site interaction pairs.

In the simulation (200 replications), power appeared generally good for large interaction effects, but smaller effects will require larger studies or consortium collaboration for realizing a sufficient power.


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March 9, 2019


Methylation, Interaction, Genome wide association, Region based association, Candidate gene association, Mediation analysis, Multi-level Gaussian model, LASSO, Adaptive W-test, Regression and random forest trees