Open AccessFeasible and Successful: Genome-Wide Interaction Analysis Involving All 1.9 × 10<sup>11</sup> Pair-Wise Interaction Tests
Author(s) -
Michael Steffens,
Tim Becker,
Thomas Sander,
Rolf Fimmers,
Christine Herold,
Daniela Höller,
Costin Leu,
Stefan Herms,
Sven Cichon,
Bastian Bohn,
Thomas Gerstner,
Michael Griebel,
Markus M. Nöthen,
Thomas F. Wienker,
Max P. Baur
Publication year - 2010
Publication title -
human heredity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.423
H-Index - 62
eISSN - 1423-0062
pISSN - 0001-5652
DOI - 10.1159/000295896
Subject(s) - genome wide association study , epistasis , genetics , missing heritability problem , gene interaction , heritability , computational biology , biology , genetic association , single nucleotide polymorphism , gene , genome , genotype
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.