The Challenges of Genome-Wide Interaction Studies: Lessons to Learn from the Analysis of HDL Blood Levels


Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.

DOI: 10.1371/journal.pone.0109290

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@inproceedings{Leeuwen2014TheCO, title={The Challenges of Genome-Wide Interaction Studies: Lessons to Learn from the Analysis of HDL Blood Levels}, author={Elisabeth M. van Leeuwen and Françoise A. S. Smouter and Tony Kam-Thong and Nazanin Karbalai and Albert V. Smith and Tamara B. Harris and Lenore J. Launer and Colleen M . Sitlani and Guo Li and Jennifer A Brody and Joshua C Bis and Charles C . White and Alok Jaiswal and Ben A. Oostra and Albert Hofman and Fernando Rivadeneira and Andr{\'e} G. Uitterlinden and Eric Boerwinkle and Christie M. Ballantyne and Vilmundur Gudnason and Bruce M . Psaty and L. Adrienne Cupples and Marjo-Riitta J{\"a}rvelin and Samuli Ripatti and Aaron Isaacs and Bertram M{\"{u}ller-Myhsok and Lennart C. Karssen and Cornelia Marja van Duijn and Joel S Bader}, booktitle={PloS one}, year={2014} }