Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer's disease

Emrin Horgusluoglu-Moloch; Kwangsik Nho; Shannon L Risacher; Sungeun Kim; Tatiana Foroud; Leslie M Shaw; John Q Trojanowski; Paul S Aisen; Ronald C Petersen; Clifford R Jack Jr; Simon Lovestone; Andrew Simmons; Michael W Weiner; Andrew J Saykin; Alzheimer's Disease Neuroimaging Initiative (ADNI)

doi:10.1016/j.neurobiolaging.2017.08.010

Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer's disease

Neurobiol Aging. 2017 Dec:60:92-103. doi: 10.1016/j.neurobiolaging.2017.08.010. Epub 2017 Aug 18.

Authors

Affiliations

¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
² Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: knho@iupui.edu.
³ 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.
⁴ Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Electrical and Computer Engineering, State University of New York Oswego, Oswego, NY, USA.
⁵ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
⁷ Department of Neurology, University of Southern California, San Diego, CA, USA.
⁸ Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA.
⁹ Department of Radiology, Mayo Clinic Minnesota, Rochester, MN, USA.
¹⁰ Institute of Psychiatry, King's College London, London, UK.
¹¹ Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, CA, USA; Department of Veterans Affairs Medical Center, San Francisco, CA, USA.
¹² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: asaykin@iu.edu.

PMID: 28941407
PMCID: PMC5774672
DOI: 10.1016/j.neurobiolaging.2017.08.010

Abstract

Alzheimer's disease (AD) patients display hippocampal atrophy, memory impairment, and cognitive decline. New neurons are generated throughout adulthood in 2 regions of the brain implicated in AD, the dentate gyrus of the hippocampus and the subventricular zone of the olfactory bulb. Disruption of this process contributes to neurodegenerative diseases including AD, and many of the molecular players in AD are also modulators of adult neurogenesis. However, the genetic mechanisms underlying adult neurogenesis in AD have been underexplored. To address this gap, we performed a gene-based association analysis in cognitively normal and impaired participants using neurogenesis pathway-related candidate genes curated from existing databases, literature mining, and large-scale genome-wide association study findings. A gene-based association analysis identified adenosine A2a receptor (ADORA2A) as significantly associated with hippocampal volume and the association between rs9608282 within ADORA2A and hippocampal volume was replicated in the meta-analysis after multiple comparison adjustments (p = 7.88 × 10^-6). The minor allele of rs9608282 in ADORA2A is associated with larger hippocampal volumes and better memory.

Keywords: ADORA2A; Alzheimer's disease; Gene-based association analysis; Hippocampal volume; Memory; NMDA-receptor antagonist; Neurogenesis.

MeSH terms

Aged
Aged, 80 and over
Alleles
Alzheimer Disease / genetics*
Alzheimer Disease / pathology*
Cognition / physiology
Cognitive Dysfunction / genetics*
Cognitive Dysfunction / pathology*
Cognitive Dysfunction / psychology
Female
Genome-Wide Association Study*
Hippocampus / pathology*
Humans
Male
Middle Aged
Neurogenesis / genetics*
Organ Size / genetics*
Receptor, Adenosine A2A / genetics*
Receptor, Adenosine A2A / physiology*

Substances

Receptor, Adenosine A2A

Abstract

MeSH terms

Substances

Grants and funding