BioData Mining (Jul 2017)
Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals
- Emily R. Holzinger,
- Shefali S. Verma,
- Carrie B. Moore,
- Molly Hall,
- Rishika De,
- Diane Gilbert-Diamond,
- Matthew B. Lanktree,
- Nathan Pankratz,
- Antoinette Amuzu,
- Amber Burt,
- Caroline Dale,
- Scott Dudek,
- Clement E. Furlong,
- Tom R. Gaunt,
- Daniel Seung Kim,
- Helene Riess,
- Suthesh Sivapalaratnam,
- Vinicius Tragante,
- Erik P.A. van Iperen,
- Ariel Brautbar,
- David S. Carrell,
- David R. Crosslin,
- Gail P. Jarvik,
- Helena Kuivaniemi,
- Iftikhar J. Kullo,
- Eric B. Larson,
- Laura J. Rasmussen-Torvik,
- Gerard Tromp,
- Jens Baumert,
- Karen J. Cruickshanks,
- Martin Farrall,
- Aroon D. Hingorani,
- G. K. Hovingh,
- Marcus E. Kleber,
- Barbara E. Klein,
- Ronald Klein,
- Wolfgang Koenig,
- Leslie A. Lange,
- Winfried Mӓrz,
- Kari E. North,
- N. Charlotte Onland-Moret,
- Alex P. Reiner,
- Philippa J. Talmud,
- Yvonne T. van der Schouw,
- James G. Wilson,
- Mika Kivimaki,
- Meena Kumari,
- Jason H. Moore,
- Fotios Drenos,
- Folkert W. Asselbergs,
- Brendan J. Keating,
- Marylyn D. Ritchie
Affiliations
- Emily R. Holzinger
- Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institute for General Medical Sciences, National Institutes of Health
- Shefali S. Verma
- The Center for Systems Genomics, The Pennsylvania State University, University Park
- Carrie B. Moore
- Department of Surgery, Duke University
- Molly Hall
- The Center for Systems Genomics, The Pennsylvania State University, University Park
- Rishika De
- Department of Genetics, Geisel School of Medicine at Dartmouth
- Diane Gilbert-Diamond
- Department of Epidemiology, Geisel School of Medicine at Dartmouth
- Matthew B. Lanktree
- Department of Medicine, McMaster University
- Nathan Pankratz
- Department of Lab Medicine and Pathology, University of Minnesota
- Antoinette Amuzu
- London School of Hygiene and Tropical Medicine
- Amber Burt
- Division of Medical Genetics, Department of Medicine, University of Washington
- Caroline Dale
- London School of Hygiene and Tropical Medicine
- Scott Dudek
- The Center for Systems Genomics, The Pennsylvania State University, University Park
- Clement E. Furlong
- Division of Medical Genetics, Department of Medicine, University of Washington
- Tom R. Gaunt
- MRC Integrative Epidemiology Unit, University of Bristol
- Daniel Seung Kim
- Division of Medical Genetics, Department of Medicine, University of Washington
- Helene Riess
- Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health
- Suthesh Sivapalaratnam
- Department of Vascular Medicine, Academic Medical Center
- Vinicius Tragante
- Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht
- Erik P.A. van Iperen
- Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute
- Ariel Brautbar
- Department of Medical Genetics, Marshfield Clinic
- David S. Carrell
- Group Health Research Institute, Group Health Cooperative
- David R. Crosslin
- Division of Medical Genetics, Department of Medicine, University of Washington
- Gail P. Jarvik
- Division of Medical Genetics, Department of Medicine, University of Washington
- Helena Kuivaniemi
- Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University
- Iftikhar J. Kullo
- Division of Cardiovascular Diseases, Mayo Clinic
- Eric B. Larson
- Group Health Research Institute, Group Health Cooperative
- Laura J. Rasmussen-Torvik
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine
- Gerard Tromp
- Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University
- Jens Baumert
- Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health
- Karen J. Cruickshanks
- Department of Population Health Sciences, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison
- Martin Farrall
- Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford
- Aroon D. Hingorani
- Department of Epidemiology and Public Health, UCL Institute of Epidemiology & Health Care, University College London
- G. K. Hovingh
- Department of Vascular Medicine, Academic Medical Center
- Marcus E. Kleber
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University
- Barbara E. Klein
- Department of Population Health Sciences, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison
- Ronald Klein
- Department of Population Health Sciences, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison
- Wolfgang Koenig
- Department of Internal Medicine II – Cardiology, University of Ulm Medical Centre
- Leslie A. Lange
- Department of Genetics, University of North Carolina School of Medicine at Chapel Hill
- Winfried Mӓrz
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University
- Kari E. North
- Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill
- N. Charlotte Onland-Moret
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht
- Alex P. Reiner
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
- Philippa J. Talmud
- MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol
- Yvonne T. van der Schouw
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht
- James G. Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center
- Mika Kivimaki
- Department of Epidemiology and Public Health, UCL Institute of Epidemiology & Health Care, University College London
- Meena Kumari
- Department of Epidemiology and Public Health, UCL Institute of Epidemiology & Health Care, University College London
- Jason H. Moore
- Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania
- Fotios Drenos
- MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol
- Folkert W. Asselbergs
- Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht
- Brendan J. Keating
- Division of Genetics, The Children’s Hospital of Philadelphia
- Marylyn D. Ritchie
- Biomedical and Translational Informatics, Geisinger Clinic
- DOI
- https://doi.org/10.1186/s13040-017-0145-5
- Journal volume & issue
-
Vol. 10,
no. 1
pp. 1 – 20
Abstract
Abstract Background The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). Results Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing. Conclusions These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.
Keywords
