Genetic analysis of quantitative phenotypes in AD and MCI: Imaging, cognition and biomarkers

Li Shen, Paul M. Thompson, Steven G. Potkin, Lars Bertram, Lindsay A. Farrer, Tatiana Foroud, Robert C. Green, Xiaolan Hu, Matthew J. Huentelman, Sungeun Kim, John S K Kauwe, Qingqin Li, Enchi Liu, Fabio Macciardi, Jason H. Moore, Leanne Munsie, Kwangsik Nho, Vijay K. Ramanan, Shannon L. Risacher, David J. StoneShanker Swaminathan, Arthur W. Toga, Michael W. Weiner, Andrew Saykin

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

The Genetics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer's disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g., APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g., FRMD6) that were later replicated on different data sets. Several other genes (e.g., APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development.

Original languageEnglish
Pages (from-to)183-207
Number of pages25
JournalBrain Imaging and Behavior
Volume8
Issue number2
DOIs
StatePublished - 2014

Fingerprint

Cognition
Alzheimer Disease
Neuroimaging
Biomarkers
Phenotype
Endophenotypes
Functional Neuroimaging
Genome-Wide Association Study
Genes
Meta-Analysis
Multivariate Analysis
Genotype

Keywords

  • Alzheimer's disease
  • Biomarker
  • Cognition
  • Genetic association study
  • Neuroimaging
  • Quantitative traits

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Behavioral Neuroscience
  • Cellular and Molecular Neuroscience
  • Cognitive Neuroscience
  • Neurology
  • Psychiatry and Mental health
  • Clinical Neurology
  • Medicine(all)

Cite this

Genetic analysis of quantitative phenotypes in AD and MCI : Imaging, cognition and biomarkers. / Shen, Li; Thompson, Paul M.; Potkin, Steven G.; Bertram, Lars; Farrer, Lindsay A.; Foroud, Tatiana; Green, Robert C.; Hu, Xiaolan; Huentelman, Matthew J.; Kim, Sungeun; Kauwe, John S K; Li, Qingqin; Liu, Enchi; Macciardi, Fabio; Moore, Jason H.; Munsie, Leanne; Nho, Kwangsik; Ramanan, Vijay K.; Risacher, Shannon L.; Stone, David J.; Swaminathan, Shanker; Toga, Arthur W.; Weiner, Michael W.; Saykin, Andrew.

In: Brain Imaging and Behavior, Vol. 8, No. 2, 2014, p. 183-207.

Research output: Contribution to journalArticle

Shen, L, Thompson, PM, Potkin, SG, Bertram, L, Farrer, LA, Foroud, T, Green, RC, Hu, X, Huentelman, MJ, Kim, S, Kauwe, JSK, Li, Q, Liu, E, Macciardi, F, Moore, JH, Munsie, L, Nho, K, Ramanan, VK, Risacher, SL, Stone, DJ, Swaminathan, S, Toga, AW, Weiner, MW & Saykin, A 2014, 'Genetic analysis of quantitative phenotypes in AD and MCI: Imaging, cognition and biomarkers', Brain Imaging and Behavior, vol. 8, no. 2, pp. 183-207. https://doi.org/10.1007/s11682-013-9262-z
Shen, Li ; Thompson, Paul M. ; Potkin, Steven G. ; Bertram, Lars ; Farrer, Lindsay A. ; Foroud, Tatiana ; Green, Robert C. ; Hu, Xiaolan ; Huentelman, Matthew J. ; Kim, Sungeun ; Kauwe, John S K ; Li, Qingqin ; Liu, Enchi ; Macciardi, Fabio ; Moore, Jason H. ; Munsie, Leanne ; Nho, Kwangsik ; Ramanan, Vijay K. ; Risacher, Shannon L. ; Stone, David J. ; Swaminathan, Shanker ; Toga, Arthur W. ; Weiner, Michael W. ; Saykin, Andrew. / Genetic analysis of quantitative phenotypes in AD and MCI : Imaging, cognition and biomarkers. In: Brain Imaging and Behavior. 2014 ; Vol. 8, No. 2. pp. 183-207.
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AU - Foroud, Tatiana

AU - Green, Robert C.

AU - Hu, Xiaolan

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AU - Kim, Sungeun

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AU - Li, Qingqin

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AU - Risacher, Shannon L.

AU - Stone, David J.

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