title: Genome-wide interaction analysis reveals replicated epistatic effects on brain structure.
abstract: The discovery of several genes that affect the risk for Alzheimer's disease ignited a worldwide search for single-nucleotide polymorphisms (SNPs), common genetic variants that affect the brain. Genome-wide search of all possible SNP-SNP interactions is challenging and rarely attempted because of the complexity of conducting approximately 10(11) pairwise statistical tests. However, recent advances in machine learning, for example, iterative sure independence screening, make it possible to analyze data sets with vastly more predictors than observations. Using an implementation of the sure independence screening algorithm (called EPISIS), we performed a genome-wide interaction analysis testing all possible SNP-SNP interactions affecting regional brain volumes measured on magnetic resonance imaging and mapped using tensor-based morphometry. We identified a significant SNP-SNP interaction between rs1345203 and rs1213205 that explains 1.9% of the variance in temporal lobe volume. We mapped the whole brain, voxelwise effects of the interaction in the Alzheimer's Disease Neuroimaging Initiative data set and separately in an independent replication data set of healthy twins (Queensland Twin Imaging). Each additional loading in the interaction effect was associated with approximately 5% greater brain regional brain volume (a protective effect) in both Alzheimer's Disease Neuroimaging Initiative and Queensland Twin Imaging samples.
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles, CA, USA.
authors.forename: Derrek P
authors.initials: DP
authors.lastname: Hibar
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles, CA, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles, CA, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Jahanshad
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles, CA, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Kohannim
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles, CA, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Hua
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles, CA, USA.
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Toga
authors.affiliation: Centre for Magnetic Resonance, School of Psychology, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Katie L
authors.initials: KL
authors.lastname: McMahon
authors.affiliation: Functional Magnetic Resonance Imaging Laboratory, School of Psychology, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Greig I
authors.initials: GI
authors.lastname: de Zubicaray
authors.affiliation: Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: Department of Radiology, UC San Francisco, San Francisco, CA, USA; Department of Medicine, UC San Francisco, San Francisco, CA, USA; Department of Psychiatry, UC San Francisco, San Francisco, CA, USA; Department of Veterans Affairs Medical Center, San Francisco, CA, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles, CA, USA. Electronic address: pthomp@usc.edu.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D004843:Epistasis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D059906:Neuroimaging / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk; D013702:Temporal Lobe / Q000473:pathology*; D014427:Twins
keywords: Epistasis; GWAS; GWIA; Genome-wide; Interaction; Sure independence screening; Tensor-based morphometry