title: Two-dimensional Enrichment Analysis for Mining High-level Imaging Genetic Associations.
abstract: Enrichment analysis has been widely applied in the genome-wide association studies (GWAS), where gene sets corresponding to biological pathways are examined for significant associations with a phenotype to help increase statistical power and improve biological interpretation. In this work, we expand the scope of enrichment analysis into brain imaging genetics, an emerging field that studies how genetic variation influences brain structure and function measured by neuroimaging quantitative traits (QT). Given the high dimensionality of both imaging and genetic data, we propose to study Imaging Genetic Enrichment Analysis (IGEA), a new enrichment analysis paradigm that jointly considers meaningful gene sets (GS) and brain circuits (BC) and examines whether any given GS-BC pair is enriched in a list of gene-QT findings. Using gene expression data from Allen Human Brain Atlas and imaging genetics data from Alzheimer's Disease Neuroimaging Initiative as test beds, we present an IGEA framework and conduct a proof-of-concept study. This empirical study identifies 12 significant high level two dimensional imaging genetics modules. Many of these modules are relevant to a variety of neurobiological pathways or neurodegenerative diseases, showing the promise of the proposal framework for providing insight into the mechanism of complex diseases.
authors.affiliation: Radiology and Imaging Sciences, Indiana University School of Medicine, IN, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yao
authors.affiliation: School of Informatics and Computing, Indiana University Indianapolis, IN, USA.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Yan
authors.affiliation: Mathematics, Rose-Hulman Institute of Technology, IN, USA.
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Biomedical Informatics, School of Medicine, University of Pennsylvania, PA, USA.
authors.forename: Kwangsik
authors.initials: K
authors.lastname: Nho
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Risacher
authors.forename: Mark
authors.initials: M
authors.lastname: Inlow
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
authors.forename: Li
authors.initials: L
authors.lastname: Shen
keywords: Imaging genetics; enrichment analysis; genome wide association study; quantitative trait