Gene Prioritization for Imaging Genetics Studies Using Gene Ontology and a Stratified False Discovery Rate Approach.
Imaging genetics is an emerging field in which the association between genes and neuroimaging-based quantitative phenotypes are used to explore the functional role of genes in neuroanatomy and neurophysiology in the context of healthy function and neuropsychiatric disorders. The main obstacle for researchers in the field is the high dimensionality of the data in both the imaging phenotypes and the genetic variants commonly typed. In this article, we develop a novel method that utilizes Gene Ontology, an online database, to select and prioritize certain genes, employing a stratified false discovery rate (sFDR) approach to investigate their associations with imaging phenotypes. sFDR has the potential to increase power in genome wide association studies (GWAS), and is quickly gaining traction as a method for multiple testing correction. Our novel approach addresses both the pressing need in genetic research to move beyond candidate gene studies, while not being overburdened with a loss of power due to multiple testing. As an example of our methodology, we perform a GWAS of hippocampal volume using both the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA2) and the Alzheimer's Disease Neuroimaging Initiative datasets. The analysis of ENIGMA2 data yielded a set of SNPs with sFDR values between 10 and 20%. Our approach demonstrates a potential method to prioritize genes based on biological systems impaired in a disease.
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental HealthToronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of TorontoToronto, ON, Canada.
Sejal
S
Patel
Cerebral Imaging Centre, Douglas Mental Health University Institute, McGill UniversityVerdun, QC, Canada; Schulich School of Medicine and Dentistry, Western UniversityLondon, ON, Canada.
Min Tae M
MT
Park
Cerebral Imaging Centre, Douglas Mental Health University Institute, McGill UniversityVerdun, QC, Canada; Department of Psychiatry, McGill UniversityMontreal, QC, Canada.
M Mallar
MM
Chakravarty
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental HealthToronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of TorontoToronto, ON, Canada; Department of Psychiatry, University of TorontoToronto, ON, Canada; Biostatistics Division, Dalla Lana School of Public Health, University of TorontoToronto, ON, Canada; Lancaster Medical School and Data Science Institute, Lancaster UniversityLancaster, UK.
Jo
J
Knight
Alzheimer's disease (AD); gene ontology network; genome wide association study (GWAS); imaging genetics; magnetic resonance imaging (MRI); stratified false discovery rate (sFDR)