title: Feasible and successful: genome-wide interaction analysis involving all 1.9 x 10(11) pair-wise interaction tests.
abstract: The Genome-Wide Association Study (GWAS) is the study design of choice for detecting common genetic risk factors for multifactorial diseases. The performance of full Genome-Wide Interaction Analyses (GWIA) has always been considered computationally challenging. Two-stage strategies to reduce the amount of numerical analysis require the detection of single marker effects or prior pathophysiological hypotheses before the analysis of interaction. This prevents the detection of pure epistatic effects. Our case-control study in idiopathic generalized epilepsy demonstrates that a full GWIA is feasible through use of data compression, specific data representation, interleaved data organization, and parallelization of the analysis on a multi-processor system. Following extensive quality control of the genotypes, our final list of top interaction hits contains only pairs of interacting SNPs with negligible marginal effects. The TOP HIT interaction was between a SNP-pair intragenic to gene DNER (chr 2) and gene CTNNA3 (chr 10). Both of these genes are functionally involved in neuronal migration, synaptogenesis, and the formation of neuronal circuits. Our results therefore indicate a possible interaction between these two genes in epileptogenesis. Results from GWAS are beginning to reveal a 'missing heritability' in complex traits and diseases. Systematic, hypothesis-free analysis of epistatic interaction (GWIA) may help to close this increasingly recognized gap in heritability.
authors.affiliation: Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.forename: Rolf
authors.initials: R
authors.lastname: Fimmers
authors.forename: Christine
authors.initials: C
authors.lastname: Herold
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Holler
authors.forename: Costin
authors.initials: C
authors.lastname: Leu
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Bastian
authors.initials: B
authors.lastname: Bohn
authors.forename: Thomas
authors.initials: T
authors.lastname: Gerstner
authors.forename: Michael
authors.initials: M
authors.lastname: Griebel
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.forename: Max P
authors.initials: MP
authors.lastname: Baur
mesh_terms: D004827:Epilepsy / Q000235:genetics; D005240:Feasibility Studies; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide