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- Title
A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects.
- Authors
Herold, Christine; Ramirez, Alfredo; Drichel, Dmitriy; Lacour, André; Vaitsiakhovich, Tatsiana; Nöthen, Markus M.; Jessen, Frank; Maier, Wolfgang; Becker, Tim
- Abstract
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 () that is not attributable to either two-way or three-way interaction.
- Subjects
SINGLE nucleotide polymorphisms; GENETIC disorders; GENOMICS; EPISTASIS (Genetics); ALLELES; ALZHEIMER'S disease; SIMULATION methods &; models
- Publication
PLoS ONE, 2013, Vol 8, Issue 10, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0078038