@article {6607,
	title = {The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels.},
	journal = {PLoS One},
	volume = {9},
	year = {2014},
	month = {2014},
	pages = {e109290},
	abstract = {<p>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{\texttimes}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 {\textperiodcentered} 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{\texttimes}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.</p>},
	keywords = {Cholesterol, HDL, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0109290},
	author = {van Leeuwen, Elisabeth M and Smouter, Fran{\c c}oise A S and Kam-Thong, Tony and Karbalai, Nazanin and Smith, Albert V and Harris, Tamara B and Launer, Lenore J and Sitlani, Colleen M and Li, Guo and Brody, Jennifer A and Bis, Joshua C and White, Charles C and Jaiswal, Alok and Oostra, Ben A and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Boerwinkle, Eric and Ballantyne, Christie M and Gudnason, Vilmundur and Psaty, Bruce M and Cupples, L Adrienne and Jarvelin, Marjo-Riitta and Ripatti, Samuli and Isaacs, Aaron and M{\"u}ller-Myhsok, Bertram and Karssen, Lennart C and van Duijn, Cornelia M}
}
