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A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects

Deviation from multiplicativity of genetic risk factors is biologically plausible and might explain why Genome-wide association studies (GWAS) so far could unravel only a portion of disease heritability. Still, evidence for SNP-SNP epistasis has rarely been reported, suggesting that 2-SNP models are...

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Autores principales: Herold, Christine, Ramirez, Alfredo, Drichel, Dmitriy, Lacour, André, Vaitsiakhovich, Tatsiana, Nöthen, Markus M., Jessen, Frank, Maier, Wolfgang, Becker, Tim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813579/
https://www.ncbi.nlm.nih.gov/pubmed/24205078
http://dx.doi.org/10.1371/journal.pone.0078038
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author Herold, Christine
Ramirez, Alfredo
Drichel, Dmitriy
Lacour, André
Vaitsiakhovich, Tatsiana
Nöthen, Markus M.
Jessen, Frank
Maier, Wolfgang
Becker, Tim
author_facet Herold, Christine
Ramirez, Alfredo
Drichel, Dmitriy
Lacour, André
Vaitsiakhovich, Tatsiana
Nöthen, Markus M.
Jessen, Frank
Maier, Wolfgang
Becker, Tim
author_sort Herold, Christine
collection PubMed
description Deviation from multiplicativity of genetic risk factors is biologically plausible and might explain why Genome-wide association studies (GWAS) so far could unravel only a portion of disease heritability. Still, evidence for SNP-SNP epistasis has rarely been reported, suggesting that 2-SNP models are overly simplistic. In this context, it was recently proposed that the genetic architecture of complex diseases could follow limiting pathway models. These models are defined by a critical risk allele load and imply multiple high-dimensional interactions. Here, we present a computationally efficient one-degree-of-freedom “supra-multiplicativity-test” (SMT) for SNP sets of size 2 to 500 that is designed to detect risk alleles whose joint effect is fortified when they occur together in the same individual. Via a simulation study we show that the SMT is powerful in the presence of threshold models, even when only about 30–45% of the model SNPs are available. In addition, we demonstrate that the SMT outperforms standard interaction analysis under recessive models involving just a few SNPs. We apply our test to 10 consensus Alzheimer’s disease (AD) susceptibility SNPs that were previously identified by GWAS and obtain evidence for supra-multiplicativity ([Image: see text]) that is not attributable to either two-way or three-way interaction.
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spelling pubmed-38135792013-11-07 A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects Herold, Christine Ramirez, Alfredo Drichel, Dmitriy Lacour, André Vaitsiakhovich, Tatsiana Nöthen, Markus M. Jessen, Frank Maier, Wolfgang Becker, Tim PLoS One Research Article Deviation from multiplicativity of genetic risk factors is biologically plausible and might explain why Genome-wide association studies (GWAS) so far could unravel only a portion of disease heritability. Still, evidence for SNP-SNP epistasis has rarely been reported, suggesting that 2-SNP models are overly simplistic. In this context, it was recently proposed that the genetic architecture of complex diseases could follow limiting pathway models. These models are defined by a critical risk allele load and imply multiple high-dimensional interactions. Here, we present a computationally efficient one-degree-of-freedom “supra-multiplicativity-test” (SMT) for SNP sets of size 2 to 500 that is designed to detect risk alleles whose joint effect is fortified when they occur together in the same individual. Via a simulation study we show that the SMT is powerful in the presence of threshold models, even when only about 30–45% of the model SNPs are available. In addition, we demonstrate that the SMT outperforms standard interaction analysis under recessive models involving just a few SNPs. We apply our test to 10 consensus Alzheimer’s disease (AD) susceptibility SNPs that were previously identified by GWAS and obtain evidence for supra-multiplicativity ([Image: see text]) that is not attributable to either two-way or three-way interaction. Public Library of Science 2013-10-30 /pmc/articles/PMC3813579/ /pubmed/24205078 http://dx.doi.org/10.1371/journal.pone.0078038 Text en © 2013 Herold et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Herold, Christine
Ramirez, Alfredo
Drichel, Dmitriy
Lacour, André
Vaitsiakhovich, Tatsiana
Nöthen, Markus M.
Jessen, Frank
Maier, Wolfgang
Becker, Tim
A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects
title A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects
title_full A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects
title_fullStr A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects
title_full_unstemmed A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects
title_short A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects
title_sort one-degree-of-freedom test for supra-multiplicativity of snp effects
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813579/
https://www.ncbi.nlm.nih.gov/pubmed/24205078
http://dx.doi.org/10.1371/journal.pone.0078038
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