title: Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans.
abstract: BACKGROUND
  Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans.
  
  
  METHODS
  Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated.
  
  
  RESULTS
  ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD.
  
  
  CONCLUSIONS
  Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge.
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: asaykin@iupui.edu.
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, IN, USA; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; School of Informatics and Computing, Indiana University, Purdue University - Indianapolis, Indianapolis, IN, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yao
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, 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, IN, USA; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kwangsik
authors.initials: K
authors.lastname: Nho
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Risacher
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Ramanan
authors.affiliation: Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Faber
authors.affiliation: Eisai Ltd., Hatfield, Hertfordshire, UK.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Sarwar
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Munsie
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Hu
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Holly D
authors.initials: HD
authors.lastname: Soares
authors.affiliation: Department of Psychiatry and Human Behavior, University of California - Irvine, Irvine, CA, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Potkin
authors.affiliation: Department of Neurology, Keck School of Medicine of USC, University of Southern California, Marina del Rey, CA, USA; Imaging Genetics Center, Keck School of Medicine of USC, University of Southern California, Marina del Rey, CA, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA; Department of Neuroscience, Brigham Young University, Provo, UT, USA.
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: Kaddurah-Daouk
authors.affiliation: Partners Center for Personalized Genetic Medicine, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.affiliation: Laboratory of Neuroimaging, Institute for Neuroimaging and Neuroinformatics, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Toga
authors.affiliation: Department of Radiology, University of California-San Francisco, San Francisco, CA, USA; Department of Medicine, University of California-San Francisco, San Francisco, CA, USA; Department of Psychiatry, University of California-San Francisco, San Francisco, CA, USA; Center for Imaging of Neurodegenerative Diseases, San Francisco VA Medical Center, San Francisco, CA, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000235:genetics*; D016206:Databases, Bibliographic / Q000706:statistics & numerical data; D018450:Disease Progression; D056726:Genetic Association Studies; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D059906:Neuroimaging
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human
keywords: Alzheimer's disease (AD); Bioethical issues; Biomarkers; Cerebrospinal fluid (CSF); Cognition; Copy number variation (CNV); DNA; Genome-wide association studies (GWAS); Magnetic resonance imaging (MRI); Memory; Mild cognitive impairment (MCI); Next generation sequencing (NGS); Positron emission tomography (PET); Precision medicine; RNA