title: Network-based analysis of genetic variants associated with hippocampal volume in Alzheimer's disease: a study of ADNI cohorts.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a neurodegenerative disease that causes dementia. While molecular basis of AD is not fully understood, genetic factors are expected to participate in the development and progression of the disease. Our goal was to uncover novel genetic underpinnings of Alzheimer's disease with a bioinformatics approach that accounts for tissue specificity.
  
  
  RESULTS
  We performed genome-wide association studies (GWAS) for hippocampal volume in two Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts. We used these GWAS in a subsequent tissue-specific network-wide association study (NetWAS), which applied nominally significant associations in the initial GWAS to identify disease relevant patterns in a functional network for the hippocampus. We compared prioritized gene lists from NetWAS and GWAS with literature curated AD-associated genes from the Online Mendelian Inheritance in Man (OMIM) database. In the ADNI-1 GWAS, where we also observed an enrichment of low p-values, NetWAS prioritized disease-gene associations in accordance with OMIM annotations. This was not observed in the ADNI-2 dataset. We provide source code to replicate these analyses as well as complete results under permissive licenses.
  
  
  CONCLUSIONS
  We performed the first analysis of hippocampal volume using NetWAS, which uses machine learning algorithms applied to tissue-specific functional interaction network to prioritize GWAS results. Our findings support the idea that tissue-specific networks may provide helpful context for understanding the etiology of common human diseases and reveal challenges that network-based approaches encounter in some datasets. Our source code and intermediate results files can facilitate the development of methods to address these challenges.
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire USA ; Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, New Hampshire USA ; Institute for Quantitative Biomedical Sciences, Dartmouth College, Hanover, New Hampshire USA.
authors.forename: Ailin
authors.initials: A
authors.lastname: Song
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana USA ; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana USA ; School of Informatics and Computing, Indiana University Indianapolis, Indianapolis, Indiana USA.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Yan
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana USA ; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana USA ; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana USA.
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana USA ; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana USA.
authors.forename: Shannon Leigh
authors.initials: SL
authors.lastname: Risacher
authors.affiliation: Simons Center for Data Analysis, Simons Foundation, New York, NY USA.
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Wong
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana USA ; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana USA ; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana USA ; School of Informatics and Computing, Indiana University Indianapolis, Indianapolis, Indiana USA ; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana USA.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire USA ; Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, New Hampshire USA ; Institute for Quantitative Biomedical Sciences, Dartmouth College, Hanover, New Hampshire USA ; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvnia USA.
authors.forename: Casey S
authors.identifier: 0000-0001-8713-9213
authors.initials: CS
authors.lastname: Greene