Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans

Andrew J Saykin; Li Shen; Xiaohui Yao; Sungeun Kim; Kwangsik Nho; Shannon L Risacher; Vijay K Ramanan; Tatiana M Foroud; Kelley M Faber; Nadeem Sarwar; Leanne M Munsie; Xiaolan Hu; Holly D Soares; Steven G Potkin; Paul M Thompson; John S K Kauwe; Rima Kaddurah-Daouk; Robert C Green; Arthur W Toga; Michael W Weiner; Alzheimer's Disease Neuroimaging Initiative

doi:10.1016/j.jalz.2015.05.009

Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans

Alzheimers Dement. 2015 Jul;11(7):792-814. doi: 10.1016/j.jalz.2015.05.009.

Authors

Andrew J Saykin¹, Li Shen², Xiaohui Yao³, Sungeun Kim⁴, Kwangsik Nho⁴, Shannon L Risacher⁴, Vijay K Ramanan⁵, Tatiana M Foroud⁶, Kelley M Faber⁷, Nadeem Sarwar⁸, Leanne M Munsie⁹, Xiaolan Hu¹⁰, Holly D Soares¹⁰, Steven G Potkin¹¹, Paul M Thompson¹², John S K Kauwe¹³, Rima Kaddurah-Daouk¹⁴, Robert C Green¹⁵, Arthur W Toga¹⁶, Michael W Weiner¹⁷; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁸ Eisai Ltd., Hatfield, Hertfordshire, UK.
⁹ Eli Lilly and Company, Indianapolis, IN, USA.
¹⁰ Bristol-Myers Squibb, Wallingford, CT, USA.
¹¹ Department of Psychiatry and Human Behavior, University of California - Irvine, Irvine, CA, USA.
¹² 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.
¹³ Department of Biology, Brigham Young University, Provo, UT, USA; Department of Neuroscience, Brigham Young University, Provo, UT, USA.
¹⁴ Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
¹⁵ 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.
¹⁶ Laboratory of Neuroimaging, Institute for Neuroimaging and Neuroinformatics, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
¹⁷ 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.

Abstract

Introduction: 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.

Discussion: 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

MeSH terms

Alzheimer Disease / diagnosis*
Alzheimer Disease / genetics*
Apolipoproteins E / genetics
Biomarkers / metabolism*
Cognitive Dysfunction / genetics*
Databases, Bibliographic / statistics & numerical data
Disease Progression
Genetic Association Studies
Humans
Membrane Transport Proteins / genetics
Mitochondrial Precursor Protein Import Complex Proteins
Neuroimaging

Substances

Apolipoproteins E
Biomarkers
Membrane Transport Proteins
Mitochondrial Precursor Protein Import Complex Proteins
TOMM40 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding