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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2013
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oai:doaj.org-article:6c5cb3d93e614073a9409faf055272652021-11-18T08:48:55ZA one-degree-of-freedom test for supra-multiplicativity of SNP effects.1932-620310.1371/journal.pone.0078038https://doaj.org/article/6c5cb3d93e614073a9409faf055272652013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24205078/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Deviation 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 ([Formula: see text]) that is not attributable to either two-way or three-way interaction.Christine HeroldAlfredo RamirezDmitriy DrichelAndré LacourTatsiana VaitsiakhovichMarkus M NöthenFrank JessenWolfgang MaierTim BeckerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 10, p e78038 (2013) |
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Medicine R Science Q |
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Medicine R Science Q Christine Herold Alfredo Ramirez Dmitriy Drichel André Lacour Tatsiana Vaitsiakhovich Markus M Nöthen Frank Jessen Wolfgang Maier Tim Becker A one-degree-of-freedom test for supra-multiplicativity of SNP effects. |
| 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 ([Formula: see text]) that is not attributable to either two-way or three-way interaction. |
| format |
article |
| author |
Christine Herold Alfredo Ramirez Dmitriy Drichel André Lacour Tatsiana Vaitsiakhovich Markus M Nöthen Frank Jessen Wolfgang Maier Tim Becker |
| author_facet |
Christine Herold Alfredo Ramirez Dmitriy Drichel André Lacour Tatsiana Vaitsiakhovich Markus M Nöthen Frank Jessen Wolfgang Maier Tim Becker |
| author_sort |
Christine Herold |
| title |
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_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_sort |
one-degree-of-freedom test for supra-multiplicativity of snp effects. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/6c5cb3d93e614073a9409faf05527265 |
| work_keys_str_mv |
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