Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome

Neuropsychobiology. 2011;64(4):183-94. doi: 10.1159/000326692. Epub 2011 Sep 9.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Case-Control Studies
  • Fatigue Syndrome, Chronic / genetics*
  • Female
  • Gene Expression Profiling / methods
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Receptors, Kainic Acid / biosynthesis
  • Receptors, Kainic Acid / genetics*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Gluk2 kainate receptor
  • NPAS2 protein, human
  • Nerve Tissue Proteins
  • Receptors, Kainic Acid