title: A one-degree-of-freedom test for supra-multiplicativity of SNP effects.
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 ([Formula: see text]) that is not attributable to either two-way or three-way interaction.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Herold
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Drichel
authors.forename: André
authors.initials: A
authors.lastname: Lacour
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Vaitsiakhovich
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
mesh_terms: D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*