Convergent Genomic Studies Identify Association of GRIK2 and NPAS2 with Chronic Fatigue SyndromeSmith 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
Mangalathu S. Rajeevan
Division of High-Consequence Pathogens and Pathology
Centers for Disease Control and Prevention, 1600 Clifton Road
Atlanta, GA 30333 (USA)
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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
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