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Journal of Molecular Neuroscience

, Volume 64, Issue 3, pp 385–396 | Cite as

In Silico Preliminary Association of Ammonia Metabolism Genes GLS, CPS1, and GLUL with Risk of Alzheimer’s Disease, Major Depressive Disorder, and Type 2 Diabetes

  • Jeddidiah W. D. Griffin
  • Ying Liu
  • Patrick C. Bradshaw
  • Kesheng Wang
Article
  • 150 Downloads

Abstract

Ammonia is a toxic by-product of protein catabolism and is involved in changes in glutamate metabolism. Therefore, ammonia metabolism genes may link a range of diseases involving glutamate signaling such as Alzheimer’s disease (AD), major depressive disorder (MDD), and type 2 diabetes (T2D). We analyzed data from a National Institute on Aging study with a family-based design to determine if 45 single nucleotide polymorphisms (SNPs) in glutaminase (GLS), carbamoyl phosphate synthetase 1 (CPS1), or glutamate-ammonia ligase (GLUL) genes were associated with AD, MDD, or T2D using PLINK software. HAPLOVIEW software was used to calculate linkage disequilibrium measures for the SNPs. Next, we analyzed the associated variations for potential effects on transcriptional control sites to identify possible functional effects of the SNPs. Of the SNPs that passed the quality control tests, four SNPs in the GLS gene were significantly associated with AD, two SNPs in the GLS gene were associated with T2D, and one SNP in the GLUL gene and three SNPs in the CPS1 gene were associated with MDD before Bonferroni correction. The in silico bioinformatic analysis suggested probable functional roles for six associated SNPs. Glutamate signaling pathways have been implicated in all these diseases, and other studies have detected similar brain pathologies such as cortical thinning in AD, MDD, and T2D. Taken together, these data potentially link GLS with AD, GLS with T2D, and CPS1 and GLUL with MDD and stimulate the generation of testable hypotheses that may help explain the molecular basis of pathologies shared by these disorders.

Keywords

Ammonia Glutamate Alzheimer’s disease Major depressive disorder Type 2 diabetes 

Notes

Acknowledgments

We acknowledge the NIH GWAS Data Repository, the Contributing Investigator(s) who contributed the phenotype data and DNA samples from his/her original study, and the primary funding organization that supported the contributing study “National Institute on Aging—Late Onset Alzheimer’s Disease Family Study: Genome-Wide Association Study for Susceptibility Loci.” The datasets used for analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000219.v1.p1. Funding support for the “Genetic Consortium for Late Onset Alzheimer’s Disease” was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer’s Disease includes a genome-wide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Genetic Consortium for Late Onset Alzheimer’s Disease. In addition, JG would like to thank Wayne C. Birchfield for directing his attention to the role of ammonia metabolism in cognitive functioning.

Author Contributions

JG and KW performed the research, and JG wrote the first draft of the manuscript. PB, KW, and YL contributed to the content of the manuscript. All authors have approved the final version of this article.

Funding Information

This study was funded by East Tennessee State University.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jeddidiah W. D. Griffin
    • 1
  • Ying Liu
    • 2
  • Patrick C. Bradshaw
    • 1
  • Kesheng Wang
    • 2
  1. 1.Department of Biomedical Sciences, Quillen College of MedicineEast Tennessee State UniversityJohnson CityUSA
  2. 2.Department of Biostatistics and Epidemiology, College of Public HealthEast Tennessee State UniversityJohnson CityUSA

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