title: The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels.
abstract: 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.
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: van Leeuwen
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Françoise A S
authors.initials: FA
authors.lastname: Smouter
authors.affiliation: Max Planck-Institute of Psychiatry, Munich, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Kam-Thong
authors.affiliation: Max Planck-Institute of Psychiatry, Munich, Germany.
authors.forename: Nazanin
authors.initials: N
authors.lastname: Karbalai
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland and University of Iceland, Reykjavik, Iceland.
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.affiliation: Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.affiliation: Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.affiliation: Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA, United States of America.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Sitlani
authors.affiliation: Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA, United States of America.
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.affiliation: Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Brody
authors.affiliation: Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA, United States of America.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Charles C
authors.initials: CC
authors.lastname: White
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Alok
authors.initials: A
authors.lastname: Jaiswal
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Departments of Epidemiology and Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: Departments of Epidemiology and Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: University of Texas Health Science Center School of Public Health, Human Genetics Center, Houston, TX, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland and University of Iceland, Reykjavik, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Departments of Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA, United States of America and Group Health Research Institute, Group Health, Seattle, WA, United States of America.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America; Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.affiliation: Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom; National Institute for Health and Welfare, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Institute of Health Sciences, University of Oulu, Oulu, Finland; Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.affiliation: Max Planck-Institute of Psychiatry, Munich, Germany; Munich Cluster für Systems Neurology (Synergy), Munich, Germany; Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Lennart C
authors.initials: LC
authors.lastname: Karssen
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
mesh_terms: D008076:Cholesterol, HDL / Q000097:blood*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D008076:Cholesterol, HDL