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

Content Provider	PubMed Central
Author	Leeuwen, Elisabeth M. Van Smouter, Françoise A. S. Tony, Kam-thong Karbalai, Nazanin Smith, Albert V. Harris, Tamara B. Launer, Lenore J. Sitlani, Colleen M. Li, Guo Brody, Jennifer A. Bis, Joshua C. White, Charles C. Jaiswal, Alok Oostra, Ben A. Hofman, Albert Rivadeneira, Fernando Uitterlinden, Andre G. Boerwinkle, Eric Ballantyne, Christie M. Gudnason, Vilmundur Psaty, Bruce M. Cupples, L. Adrienne Järvelin, Marjo-riitta Ripatti, Samuli Isaacs, Aaron Bertram, Müller-myhsok Karssen, Lennart C. Duijn, Cornelia M. Van
Editor	Bader, Joel S.
Copyright Year	2014
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 (N total = 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.
Related Links	http://dx.doi.org/10.1371/journal.pone.0109290
Starting Page	109290
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	10
Volume Number	9
Language	English
Publisher	Public Library of Science
Publisher Date	2014-10-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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