Convergent genomic studies identify association of GRIK2 andNPAS2 with Chronic Fatigue Syndrome------------------------------------------------------------
Alicia K. Smith(a), Hong Fang(b), Toni Whistler(a), ElizabethR. Unger(a), Mangalathu S. Rajeevan(a,*)a Division of High-Consequence Pathogens and Pathology, Centersfor Disease Control and Prevention, Atlanta, Ga., andb Z-Tech Corporation, an ICF International Company at NCTR/Foodand Drug Administration, Jefferson, Ark., USA* Author Contacts - Mangalathu S. RajeevanDivision of High-Consequence Pathogens and PathologyCenters for Disease Control and Prevention, 1600 Clifton RoadAtlanta, GA 30333 (USA)Tel. +1 404 639 2931, E-Mail mor4@cdc.gov
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. ResultsSixty-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.
Key Words: Chronic fatigue syndrome - Genome-wide association - Gene expression - GRIK2 - NPAS2 - Glutamatergic neurotransmission - Circadian rhythm - Orexin signaling
View attachment Convergent genomic studies identify association of GRIK2 andNPAS2 with Chronic Fatigue Syndrome.pdf
Alicia K. Smith(a), Hong Fang(b), Toni Whistler(a), ElizabethR. Unger(a), Mangalathu S. Rajeevan(a,*)a Division of High-Consequence Pathogens and Pathology, Centersfor Disease Control and Prevention, Atlanta, Ga., andb Z-Tech Corporation, an ICF International Company at NCTR/Foodand Drug Administration, Jefferson, Ark., USA* Author Contacts - Mangalathu S. RajeevanDivision of High-Consequence Pathogens and PathologyCenters for Disease Control and Prevention, 1600 Clifton RoadAtlanta, GA 30333 (USA)Tel. +1 404 639 2931, E-Mail mor4@cdc.gov
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. ResultsSixty-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.
Key Words: Chronic fatigue syndrome - Genome-wide association - Gene expression - GRIK2 - NPAS2 - Glutamatergic neurotransmission - Circadian rhythm - Orexin signaling
View attachment Convergent genomic studies identify association of GRIK2 andNPAS2 with Chronic Fatigue Syndrome.pdf