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Table of Contents
Vol. 64, No. 4, 2011
Issue release date: September 2011
Section title: Original Paper
Free Access
Neuropsychobiology 2011;64:183–194
(DOI:10.1159/000326692)

Convergent Genomic Studies Identify Association of GRIK2 and NPAS2 with Chronic Fatigue Syndrome

Smith A.K.a, 1 · Fang H.b · Whistler T.a · Unger E.R.a · Rajeevan M.S.a
aDivision of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Ga., and bZ-Tech Corporation, an ICF International Company at NCTR/Food and Drug Administration, Jefferson, Ark., USA
email Corresponding Author

Abstract

Background: There is no consistent evidence of specific gene(s) or molecular pathways that contribute to the pathogenesis, therapeutic intervention or diagnosis of chronic fatigue syndrome (CFS). While multiple studies support a role for genetic variation in CFS, genome-wide efforts to identify associated loci remain unexplored. We employed a novel convergent functional genomics approach that incorporates the findings from single-nucleotide polymorphism (SNP) and mRNA expression studies to identify associations between CFS and novel candidate genes for further investigation. Methods: We evaluated 116,204 SNPs in 40 CFS and 40 nonfatigued control subjects along with mRNA expression of 20,160 genes in a subset of these subjects (35 CFS subjects and 27 controls) derived from a population-based study. Results: Sixty-five SNPs were nominally associated with CFS (p < 0.001), and 165 genes were differentially expressed (≧4-fold; p ≤ 0.05) in peripheral blood mononuclear cells of CFS subjects. Two genes, glutamate receptor, ionotropic, kinase 2 (GRIK2) and neuronal PAS domain protein 2 (NPAS2), were identified by both SNP and gene expression analyses. Subjects with the G allele of rs2247215 (GRIK2) were more likely to have CFS (p = 0.0005), and CFS subjects showed decreased GRIK2 expression (10-fold; p = 0.015). Subjects with the T allele of rs356653 (NPAS2) were more likely to have CFS (p = 0.0007), and NPAS2 expression was increased (10-fold; p = 0.027) in those with CFS. Conclusion: Using an integrated genomic strategy, this study suggests a possible role for genes involved in glutamatergic neurotransmission and circadian rhythm in CFS and supports further study of novel candidate genes in independent populations of CFS subjects.

© 2011 S. Karger AG, Basel


  

Key Words

  • Chronic fatigue syndrome
  • Genome-wide association
  • Gene expression
  • GRIK2
  • NPAS2
  • Glutamatergic neurotransmission
  • Circadian rhythm
  • Orexin signaling

References

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    External Resources

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Author Contacts

Mangalathu S. Rajeevan
Division of High-Consequence Pathogens and Pathology
Centers for Disease Control and Prevention, 1600 Clifton Road
Atlanta, GA 30333 (USA)
Tel. +1 404 639 2931, E-Mail mor4@cdc.gov

  

Article Information

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency.

Received: August 26, 2010
Accepted after revision: February 21, 2011
Published online: September 9, 2011
Number of Print Pages : 12
Number of Figures : 0, Number of Tables : 2, Number of References : 60
Additional supplementary material is available online - Number of Parts : 3

  

Publication Details

Neuropsychobiology (International Journal of Experimental and Clinical Research in Biological Psychiatry, Pharmacopsychiatry, Biological Psychology/Pharmacopsychology and Pharmacoelectroencephalography)

Vol. 64, No. 4, Year 2011 (Cover Date: September 2011)

Journal Editor: Strik W. (Bern)
ISSN: 0302-282X (Print), eISSN: 1423-0224 (Online)

For additional information: http://www.karger.com/NPS


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: There is no consistent evidence of specific gene(s) or molecular pathways that contribute to the pathogenesis, therapeutic intervention or diagnosis of chronic fatigue syndrome (CFS). While multiple studies support a role for genetic variation in CFS, genome-wide efforts to identify associated loci remain unexplored. We employed a novel convergent functional genomics approach that incorporates the findings from single-nucleotide polymorphism (SNP) and mRNA expression studies to identify associations between CFS and novel candidate genes for further investigation. Methods: We evaluated 116,204 SNPs in 40 CFS and 40 nonfatigued control subjects along with mRNA expression of 20,160 genes in a subset of these subjects (35 CFS subjects and 27 controls) derived from a population-based study. Results: Sixty-five SNPs were nominally associated with CFS (p < 0.001), and 165 genes were differentially expressed (≧4-fold; p ≤ 0.05) in peripheral blood mononuclear cells of CFS subjects. Two genes, glutamate receptor, ionotropic, kinase 2 (GRIK2) and neuronal PAS domain protein 2 (NPAS2), were identified by both SNP and gene expression analyses. Subjects with the G allele of rs2247215 (GRIK2) were more likely to have CFS (p = 0.0005), and CFS subjects showed decreased GRIK2 expression (10-fold; p = 0.015). Subjects with the T allele of rs356653 (NPAS2) were more likely to have CFS (p = 0.0007), and NPAS2 expression was increased (10-fold; p = 0.027) in those with CFS. Conclusion: Using an integrated genomic strategy, this study suggests a possible role for genes involved in glutamatergic neurotransmission and circadian rhythm in CFS and supports further study of novel candidate genes in independent populations of CFS subjects.

© 2011 S. Karger AG, Basel


  

Author Contacts

Mangalathu S. Rajeevan
Division of High-Consequence Pathogens and Pathology
Centers for Disease Control and Prevention, 1600 Clifton Road
Atlanta, GA 30333 (USA)
Tel. +1 404 639 2931, E-Mail mor4@cdc.gov

  

Article Information

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency.

Received: August 26, 2010
Accepted after revision: February 21, 2011
Published online: September 9, 2011
Number of Print Pages : 12
Number of Figures : 0, Number of Tables : 2, Number of References : 60
Additional supplementary material is available online - Number of Parts : 3

  

Publication Details

Neuropsychobiology (International Journal of Experimental and Clinical Research in Biological Psychiatry, Pharmacopsychiatry, Biological Psychology/Pharmacopsychology and Pharmacoelectroencephalography)

Vol. 64, No. 4, Year 2011 (Cover Date: September 2011)

Journal Editor: Strik W. (Bern)
ISSN: 0302-282X (Print), eISSN: 1423-0224 (Online)

For additional information: http://www.karger.com/NPS


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 8/26/2010
Accepted: 2/21/2011
Published online: 9/9/2011
Issue release date: September 2011

Number of Print Pages: 12
Number of Figures: 0
Number of Tables: 2

ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)

For additional information: http://www.karger.com/NPS


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Klimas NG, Koneru AO: Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions. Curr Rheumatol Rep 2007;9:482–487.
  2. Togo F, Natelson BH, Cherniack NS, FitzGibbons J, Garcon C, Rapoport DM: Sleep structure and sleepiness in chronic fatigue syndrome with or without coexisting fibromyalgia. Arthritis Res Ther 2008;10:R56.
  3. Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ: Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiology 2007;55:112–120.
  4. Smith AK, Dimulescu I, Falkenberg VR, Narasimhan S, Heim C, Vernon SD, Rajeevan MS: Genetic evaluation of the serotonergic system in chronic fatigue syndrome. Psychoneuroendocrinology 2008;33:188–197.
  5. Sullivan PF, Evengard B, Jacks A, Pedersen NL: Twin analyses of chronic fatigue in a Swedish national sample. Psychol Med 2005;35:1327–1336.
  6. van de Putte EM, van Doornen LJ, Engelbert RH, Kuis W, Kimpen JL, Uiterwaal CS: Mirrored symptoms in mother and child with chronic fatigue syndrome. Pediatrics 2006;117:2074–2079.
  7. Kerr JR: Gene profiling of patients with chronic fatigue syndrome/myalgic encephalomyelitis. Curr Rheumatol Rep 2008;10:482–491.
  8. Rajeevan MS, Smith AK, Dimulescu I, Unger ER, Vernon SD, Heim C, Reeves WC: Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome. Genes Brain Behav 2007;6:167–176.
  9. Saiki T, Kawai T, Morita K, Ohta M, Saito T, Rokutan K, Ban N: Identification of marker genes for differential diagnosis of chronic fatigue syndrome. Mol Med 2008;14:599–607.
  10. Sorensen B, Jones JF, Vernon SD, Rajeevan MS: Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Mol Med 2008;15:34–42.
  11. Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005;10:40–68.
  12. Middleton FA, Rosenow C, Vailaya A, Kuchinsky A, Pato MT, Pato CN: Integrating genetic, functional genomic, and bioinformatics data in a systems biology approach to complex diseases: application to schizophrenia. Methods Mol Biol 2007;401:337–364.
  13. Vawter MP, Atz ME, Rollins BL, Cooper-Casey KM, Shao L, Byerley WF: Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia. Hum Genet 2006;119:558–570.
  14. Jiao H, Kaaman M, Dungner E, Kere J, Arner P, Dahlman I: Association analysis of positional obesity candidate genes based on integrated data from transcriptomics and linkage analysis. Int J Obes (Lond) 2008;32:816–825.
  15. Glinsky GV: Integration of HapMap-based SNP pattern analysis and gene expression profiling reveals common SNP profiles for cancer therapy outcome predictor genes. Cell Cycle 2006;5:2613–2625.
  16. Huang RS, Duan S, Bleibel WK, Kistner EO, Zhang W, Clark TA, Chen TX, Schweitzer AC, Blume JE, Cox NJ, Dolan ME: A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity. Proc Natl Acad Sci USA 2007;104:9758–9763.
  17. Kurian SM, Le-Niculescu H, Patel SD, Bertram D, Davis J, Dike C Yehyawi N, Lysaker P, Dustin J, Caligiuri M, Lohr J, Lahiri DK, Nurnberger JI Jr, Faraone SV, Geyer MA, Tsuang MT, Schork NJ, Salomon DR, Niculescu AB: Identification of blood biomarkers for psychosis using convergent functional genomics. Mol Psychiatry 2011;16:37–58.
  18. Le-Niculescu H, Patel SD, Bhat M, Kuczenski R, Faraone SV, Tsuang MT, McMahon FJ, Schork NJ, Nurnberger JI Jr, Niculescu AB 3rd: Convergent functional genomics of genome-wide association data for bipolar disorder: comprehensive identification of candidate genes, pathways and mechanisms. Am J Med Genet B Neuropsychiatr Genet 2009;150B:155–181.
  19. Le-Niculescu H, Kurian SM, Yehyawi N, Dike C, Patel SD, Edenberg HJ, Tsuang MT, Salomon DR, Nurnberger JI Jr, Niculescu AB: Identifying blood biomarkers for mood disorders using convergent functional genomics. Mol Psychiatry 2009;14:156–174.
  20. Niculescu AB, Le-Niculescu H: The P-value illusion: how to improve (psychiatric) genetic studies. Am J Med Genet B Neuropsychiatr Genet 2010;153B:847–849.
  21. Niculescu AB, Le-Niculescu H: Convergent functional genomics: what we have learned and can learn about genes, pathways, and mechanisms. Neuropsychopharmacology 2010;35:355–356.
  22. Achiron A, Gurevich M: Peripheral blood gene expression signature mirrors central nervous system disease: the model of multiple sclerosis. Autoimmun Rev 2006;5:517–522.
  23. Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C: Chronic fatigue syndrome – a clinically empirical approach to its definition and study. BMC Med 2005;3:19.
  24. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121:953–959.
  25. Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER; International Chronic Fatigue Syndrome Study Group: Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res 2003;3:25.
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