title: Characterizing genetic interactions in human disease association studies using statistical epistasis networks.
abstract: BACKGROUND
  Epistasis is recognized ubiquitous in the genetic architecture of complex traits such as disease susceptibility. Experimental studies in model organisms have revealed extensive evidence of biological interactions among genes. Meanwhile, statistical and computational studies in human populations have suggested non-additive effects of genetic variation on complex traits. Although these studies form a baseline for understanding the genetic architecture of complex traits, to date they have only considered interactions among a small number of genetic variants. Our goal here is to use network science to determine the extent to which non-additive interactions exist beyond small subsets of genetic variants. We infer statistical epistasis networks to characterize the global space of pairwise interactions among approximately 1500 Single Nucleotide Polymorphisms (SNPs) spanning nearly 500 cancer susceptibility genes in a large population-based study of bladder cancer.
  
  
  RESULTS
  The statistical epistasis network was built by linking pairs of SNPs if their pairwise interactions were stronger than a systematically derived threshold. Its topology clearly differentiated this real-data network from networks obtained from permutations of the same data under the null hypothesis that no association exists between genotype and phenotype. The network had a significantly higher number of hub SNPs and, interestingly, these hub SNPs were not necessarily with high main effects. The network had a largest connected component of 39 SNPs that was absent in any other permuted-data networks. In addition, the vertex degrees of this network were distinctively found following an approximate power-law distribution and its topology appeared scale-free.
  
  
  CONCLUSIONS
  In contrast to many existing techniques focusing on high main-effect SNPs or models of several interacting SNPs, our network approach characterized a global picture of gene-gene interactions in a population-based genetic data. The network was built using pairwise interactions, and its distinctive network topology and large connected components indicated joint effects in a large set of SNPs. Our observations suggested that this particular statistical epistasis network captured important features of the genetic architecture of bladder cancer that have not been described previously.
authors.affiliation: Department of Genetics, Dartmouth Medical School, Dartmouth College, Lebanon, NH, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Hu
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Sinnott-Armstrong
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Kiralis
authors.forename: Angeline S
authors.initials: AS
authors.lastname: Andrew
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D004843:Epistasis, Genetic; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009513:New Hampshire; D020641:Polymorphism, Single Nucleotide; D001749:Urinary Bladder Neoplasms / Q000235:genetics*