Convergent Genomic Studies Identify Association of GRIK2 and NPAS2 with Chronic Fatigue Syndrome
– Source: Neuropsychobiology, Sep 9, 2011
By Alicia K Smith, et al.
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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.
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.
• Sixty-five SNPs were nominally associated with CFS (p ! 0.001),
• And 165 genes were differentially expressed ( 6 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 [important for learning and memory] and circadian rhythm [wake sleep cycle] in CFS
• And supports further study of novel candidate genes in independent populations of CFS subjects.
Source: Neuropsychobiology, Sep 9, 2011. 64:183–194. DOI: 10.1159/000326692, by Smith AK, Fang H, Whistler T, Unger ER, Rajeevan MS. Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia; Z-Tech Corporation, an ICF International Company at NCTR/Food and Drug Administration, Jefferson, Arkansas, USA.