title: Efficient strategy for detecting gene × gene joint action and its application in schizophrenia.
abstract: We propose a new approach to detect gene × gene joint action in genome-wide association studies (GWASs) for case-control designs. This approach offers an exhaustive search for all two-way joint action (including, as a special case, single gene action) that is computationally feasible at the genome-wide level and has reasonable statistical power under most genetic models. We found that the presence of any gene × gene joint action may imply differences in three types of genetic components: the minor allele frequencies and the amounts of Hardy-Weinberg disequilibrium may differ between cases and controls, and between the two genetic loci the degree of linkage disequilibrium may differ between cases and controls. Using Fisher's method, it is possible to combine the different sources of genetic information in an overall test for detecting gene × gene joint action. The proposed statistical analysis is efficient and its simplicity makes it applicable to GWASs. In the current study, we applied the proposed approach to a GWAS on schizophrenia and found several potential gene × gene interactions. Our application illustrates the practical advantage of the proposed method.
authors.affiliation: Department of Applied Statistics, Chung-Ang University, Seoul, Korea; Research Center for Data Science, Chung-Ang University, Seoul, Korea.
authors.forename: Sungho
authors.initials: S
authors.lastname: Won
authors.forename: Min-Seok
authors.initials: MS
authors.lastname: Kwon
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.forename: Suyeon
authors.initials: S
authors.lastname: Park
authors.forename: Changsoon
authors.initials: C
authors.lastname: Park
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kihara
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Roel
authors.initials: R
authors.lastname: Ophoff
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Max
authors.initials: M
authors.lastname: Baur
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: A
authors.initials: A
authors.lastname: Hofmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
mesh_terms: D016022:Case-Control Studies; D004843:Epistasis, Genetic / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D005796:Genes; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
keywords: Hardy-Weinberg disequilibrium; gene × gene joint action; linkage disequilibrium; minor allele frequency