<i>Background:</i> 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. <i>Methods:</i> 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. <i>Results:</i> 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<i> (GRIK2)</i> and neuronal PAS domain protein 2<i> (NPAS2),</i> were identified by both SNP and gene expression analyses. Subjects with the G allele of rs2247215 <i>(GRIK2)</i> were more likely to have CFS (p = 0.0005), and CFS subjects showed decreased <i>GRIK2</i> expression (10-fold; p = 0.015). Subjects with the T allele of rs356653 <i>(NPAS2)</i> were more likely to have CFS (p = 0.0007), and <i>NPAS2</i> expression was increased (10-fold; p = 0.027) in those with CFS. <i>Conclusion:</i> 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.