Two-dimensional enrichment analysis for mining high-level imaging genetic associations

Enrichment analysis has been widely applied in the genome-wide association studies, 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 25 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.

[1]  R. Sharan,et al.  Expander: from expression microarrays to networks and functions , 2010, Nature Protocols.

[2]  P. Khatri,et al.  Global functional profiling of gene expression. , 2003, Genomics.

[3]  Jason H. Moore,et al.  Alzheimer's Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans , 2010, Alzheimer's & Dementia.

[4]  M. Gill,et al.  Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility , 2011, Molecular Psychiatry.

[5]  Fillia Makedon,et al.  Fast Nonnegative Matrix Tri-Factorization for Large-Scale Data Co-Clustering , 2011, IJCAI.

[6]  J. Hirschhorn Genomewide association studies--illuminating biologic pathways. , 2009, The New England journal of medicine.

[7]  Johnny S. H. Kwan,et al.  GATES: a rapid and powerful gene-based association test using extended Simes procedure. , 2011, American journal of human genetics.

[8]  P. Visscher,et al.  A versatile gene-based test for genome-wide association studies. , 2010, American journal of human genetics.

[9]  Hyunju Lee,et al.  A Computational Approach to Identifying Gene-microRNA Modules in Cancer , 2015, PLoS Comput. Biol..

[10]  Sangsoo Kim,et al.  GSA-SNP: a general approach for gene set analysis of polymorphisms , 2010, Nucleic Acids Res..

[11]  Purvesh Khatri,et al.  Ontological analysis of gene expression data: current tools, limitations, and open problems , 2005, Bioinform..

[12]  Shannon L. Risacher,et al.  Two-Dimensional Enrichment Analysis for Mining High-Level Imaging Genetic Associations , 2015, BIH.

[13]  Jason H. Moore,et al.  Genetic analysis of quantitative phenotypes in AD and MCI: imaging, cognition and biomarkers , 2013, Brain Imaging and Behavior.

[14]  岩坪 威,et al.  Alzheimer's Disease Neuroimaging Initiative (ADNI)の最新情報 (特集 アルツハイマー病の根本治療を目指す最近の進歩) , 2012 .

[15]  S. DeKosky,et al.  Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease , 2011, Neurology.

[16]  P. Khatri,et al.  Global functional profiling of gene expression ? ? This work was funded in part by a Sun Microsystem , 2003 .

[17]  Shannon L. Risacher,et al.  Transcriptome-guided amyloid imaging genetic analysis via a novel structured sparse learning algorithm , 2014, Bioinform..

[18]  I. Bezprozvanny Calcium signaling and neurodegenerative diseases. , 2009, Trends in molecular medicine.

[19]  Michael W. Weiner,et al.  Genome-wide pathway analysis of memory impairment in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks , 2012, Brain Imaging and Behavior.

[20]  Purvesh Khatri,et al.  Onto-Tools, the toolkit of the modern biologist: Onto-Express, Onto-Compare, Onto-Design and Onto-Translate , 2003, Nucleic Acids Res..

[21]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Delgado,et al.  Motivation-dependent responses in the human caudate nucleus. , 2004, Cerebral cortex.

[23]  Dong Liu,et al.  DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes , 2014, Nucleic acids research.

[24]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[25]  D. Butterfield,et al.  Multifunctional roles of enolase in Alzheimer’s disease brain: beyond altered glucose metabolism , 2009, Journal of neurochemistry.

[26]  M. Weiner,et al.  Influence of Genetic Variation on Plasma Protein Levels in Older Adults Using a Multi-Analyte Panel , 2013, PloS one.

[27]  Chris H. Q. Ding,et al.  Correlated Protein Function Prediction via Maximization of Data-Knowledge Consistency , 2014, RECOMB.

[28]  Allan R. Jones,et al.  Large-Scale Cellular-Resolution Gene Profiling in Human Neocortex Reveals Species-Specific Molecular Signatures , 2012, Cell.

[29]  Jason H. Moore,et al.  Pathway analysis of genomic data: concepts, methods, and prospects for future development. , 2012, Trends in genetics : TIG.

[30]  Robert R. Sokal,et al.  A statistical method for evaluating systematic relationships , 1958 .

[31]  Simon Heath,et al.  Implication of the immune system in Alzheimer's disease: evidence from genome-wide pathway analysis. , 2010, Journal of Alzheimer's disease : JAD.

[32]  Andrey Alexeyenko,et al.  Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease , 2010, Journal of Human Genetics.

[33]  Katia Charland,et al.  Caffeine for treatment of Parkinson disease , 2012, Neurology.