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 BrautbarDavid S. Carrell, David R. Crosslin, Gail P. Jarvik, Helena Kuivaniemi, Iftikhar Jan 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 MOrz, 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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Article number25
JournalBioData Mining
Volume10
Issue number1
DOIs
StatePublished - Jul 24 2017

Fingerprint

Single nucleotide Polymorphism
Nucleotides
Lipids
Polymorphism
Replication
Single Nucleotide Polymorphism
Cholesterol
Lipoproteins
Interaction
Testing
Filter
Biofilters
Medical Genetics
Pairwise
LDL Cholesterol
HDL Cholesterol
Triglycerides
Pipelines
Genes
Multiple Testing

Keywords

  • Computational genetics
  • Genetic epidemiology
  • Genetics
  • Interactions
  • Lipids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Computer Science Applications
  • Computational Theory and Mathematics
  • Computational Mathematics

Cite this

Holzinger, E. R., Verma, S. S., Moore, C. B., Hall, M., De, R., Gilbert-Diamond, D., ... Ritchie, M. D. (2017). Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals. BioData Mining, 10(1), [25]. https://doi.org/10.1186/s13040-017-0145-5

Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals. / Holzinger, Emily R.; Verma, Shefali S.; Moore, Carrie B.; Hall, Molly; De, Rishika; Gilbert-Diamond, Diane; Lanktree, Matthew B.; Pankratz, Nathan; Amuzu, Antoinette; Burt, Amber; Dale, Caroline; Dudek, Scott; Furlong, Clement E.; Gaunt, Tom R.; Kim, Daniel Seung; Riess, Helene; Sivapalaratnam, Suthesh; Tragante, Vinicius; Van Iperen, Erik P.A.; Brautbar, Ariel; Carrell, David S.; Crosslin, David R.; Jarvik, Gail P.; Kuivaniemi, Helena; Kullo, Iftikhar Jan; Larson, Eric B.; Rasmussen-Torvik, Laura J.; Tromp, Gerard; Baumert, Jens; Cruickshanks, Karen J.; Farrall, Martin; Hingorani, Aroon D.; Hovingh, G. K.; Kleber, Marcus E.; Klein, Barbara E.; Klein, Ronald; Koenig, Wolfgang; Lange, Leslie A.; MOrz, Winfried; North, Kari E.; Charlotte Onland-Moret, N.; Reiner, Alex P.; Talmud, Philippa J.; Van Der Schouw, Yvonne T.; Wilson, James G.; Kivimaki, Mika; Kumari, Meena; Moore, Jason H.; Drenos, Fotios; Asselbergs, Folkert W.; Keating, Brendan J.; Ritchie, Marylyn D.

In: BioData Mining, Vol. 10, No. 1, 25, 24.07.2017.

Research output: Contribution to journalArticle

Holzinger, ER, Verma, SS, Moore, CB, Hall, M, De, R, Gilbert-Diamond, D, Lanktree, MB, Pankratz, N, Amuzu, A, Burt, A, Dale, C, Dudek, S, Furlong, CE, Gaunt, TR, Kim, DS, Riess, H, Sivapalaratnam, S, Tragante, V, Van Iperen, EPA, Brautbar, A, Carrell, DS, Crosslin, DR, Jarvik, GP, Kuivaniemi, H, Kullo, IJ, Larson, EB, Rasmussen-Torvik, LJ, Tromp, G, Baumert, J, Cruickshanks, KJ, Farrall, M, Hingorani, AD, Hovingh, GK, Kleber, ME, Klein, BE, Klein, R, Koenig, W, Lange, LA, MOrz, W, North, KE, Charlotte Onland-Moret, N, Reiner, AP, Talmud, PJ, Van Der Schouw, YT, Wilson, JG, Kivimaki, M, Kumari, M, Moore, JH, Drenos, F, Asselbergs, FW, Keating, BJ & Ritchie, MD 2017, 'Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals', BioData Mining, vol. 10, no. 1, 25. https://doi.org/10.1186/s13040-017-0145-5
Holzinger, Emily R. ; Verma, Shefali S. ; Moore, Carrie B. ; Hall, Molly ; De, Rishika ; Gilbert-Diamond, Diane ; Lanktree, Matthew B. ; Pankratz, Nathan ; Amuzu, Antoinette ; Burt, Amber ; Dale, Caroline ; Dudek, Scott ; Furlong, Clement E. ; Gaunt, Tom R. ; Kim, Daniel Seung ; Riess, Helene ; Sivapalaratnam, Suthesh ; Tragante, Vinicius ; Van Iperen, Erik P.A. ; Brautbar, Ariel ; Carrell, David S. ; Crosslin, David R. ; Jarvik, Gail P. ; Kuivaniemi, Helena ; Kullo, Iftikhar Jan ; Larson, Eric B. ; Rasmussen-Torvik, Laura J. ; Tromp, Gerard ; Baumert, Jens ; Cruickshanks, Karen J. ; Farrall, Martin ; Hingorani, Aroon D. ; Hovingh, G. K. ; Kleber, Marcus E. ; Klein, Barbara E. ; Klein, Ronald ; Koenig, Wolfgang ; Lange, Leslie A. ; MOrz, Winfried ; North, Kari E. ; Charlotte Onland-Moret, N. ; Reiner, Alex P. ; Talmud, Philippa J. ; Van Der Schouw, Yvonne T. ; Wilson, James G. ; Kivimaki, Mika ; Kumari, Meena ; Moore, Jason H. ; Drenos, Fotios ; Asselbergs, Folkert W. ; Keating, Brendan J. ; Ritchie, Marylyn D. / Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals. In: BioData Mining. 2017 ; Vol. 10, No. 1.
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AU - Holzinger, Emily R.

AU - Verma, Shefali S.

AU - Moore, Carrie B.

AU - Hall, Molly

AU - De, Rishika

AU - Gilbert-Diamond, Diane

AU - Lanktree, Matthew B.

AU - Pankratz, Nathan

AU - Amuzu, Antoinette

AU - Burt, Amber

AU - Dale, Caroline

AU - Dudek, Scott

AU - Furlong, Clement E.

AU - Gaunt, Tom R.

AU - Kim, Daniel Seung

AU - Riess, Helene

AU - Sivapalaratnam, Suthesh

AU - Tragante, Vinicius

AU - Van Iperen, Erik P.A.

AU - Brautbar, Ariel

AU - Carrell, David S.

AU - Crosslin, David R.

AU - Jarvik, Gail P.

AU - Kuivaniemi, Helena

AU - Kullo, Iftikhar Jan

AU - Larson, Eric B.

AU - Rasmussen-Torvik, Laura J.

AU - Tromp, Gerard

AU - Baumert, Jens

AU - Cruickshanks, Karen J.

AU - Farrall, Martin

AU - Hingorani, Aroon D.

AU - Hovingh, G. K.

AU - Kleber, Marcus E.

AU - Klein, Barbara E.

AU - Klein, Ronald

AU - Koenig, Wolfgang

AU - Lange, Leslie A.

AU - MOrz, Winfried

AU - North, Kari E.

AU - Charlotte Onland-Moret, N.

AU - Reiner, Alex P.

AU - Talmud, Philippa J.

AU - Van Der Schouw, Yvonne T.

AU - Wilson, James G.

AU - Kivimaki, Mika

AU - Kumari, Meena

AU - Moore, Jason H.

AU - Drenos, Fotios

AU - Asselbergs, Folkert W.

AU - Keating, Brendan J.

AU - Ritchie, Marylyn D.

PY - 2017/7/24

Y1 - 2017/7/24

N2 - 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.

AB - 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.

KW - Computational genetics

KW - Genetic epidemiology

KW - Genetics

KW - Interactions

KW - Lipids

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