Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract

Myalgic encephalomyelitis, also known as chronic fatigue syndrome or ME/CFS, is a multifactorial and debilitating disease that has an impact on over 4 million people in the United States alone. The pathogenesis of ME/CFS remains largely unknown; however, a genetic predisposition has been suggested. In the present study, we used a DNA single-nucleotide polymorphism (SNP) chip representing over 906,600 known SNPs to analyze DNA from ME/CFS subjects and healthy controls. To the best of our knowledge, this study represents the most comprehensive genome-wide association study (GWAS) of an ME/CFS cohort conducted to date. Here 442 SNPs were identified as candidates for association with ME/CFS (adjusted P-value<0.05). Whereas the majority of these SNPs are represented in non-coding regions of the genome, 12 SNPs were identified in the coding region of their respective gene. Among these, two candidate SNPs resulted in missense substitutions, one in a pattern recognition receptor and the other in an uncharacterized coiled-coil domain-containing protein. We also identified five SNPs that cluster in the non-coding regions of T-cell receptor loci. Further examination of these polymorphisms may help identify contributing factors to the pathophysiology of ME/CFS, as well as categorize potential targets for medical intervention strategies.

Genome-Epigenome Interactions Associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Generalized gene-set analysis of the SNP data in MAGMA did not identify any gene-set 344 significantly enriched in either our data, or the data from Schlauch et al (2016). 345 346 Characterisation of SNP rs11712777 347 We used a variety of online reference resources to characterize the current knowledge of 348 rs11712777, and how it may influence ME/CFS phenotype (see Methods section).…”

A novel mutation in Slc2a4 as a mouse model of fatigue

“…Mice from two N ‐ethyl‐ N ‐nitrosourea (ENU) lines show abnormal, low amplitude voluntary wheel‐running activity patterns. Circadian activity patterns are double plotted for ease of visualization, with each horizontal line representing 48 hours and successive days plotted along the Y‐axis. Wheel revolutions are depicted as black marks on the horizontal lines.…”

“…Polymorphisms in several genes (eg, the adrenergic receptor a1 ( ADRA1A ), the serotonin transporter ( SLC6A4 ) or receptor ( HTR2A ), tyrosine hydroxylase ( TH ), corticosteroid‐binding globulin ( CBG ), corticotropin releasing hormone receptor 1 ( CRHR1 ), the cytokine IL‐1B, neuronal PAS domain protein 2 ( NPAS2 ), the nuclear receptor subfamily 3; group C, member 1 glucocorticoid receptor ( NR3C1 ) and the glutamate receptor‐ionotropic kinase 2 ( GRIK2 ) have all been linked to either the occurrence or the severity of fatigue symptomology in humans . Furthermore, a recent study comparing CFS patients to healthy controls identified 442 additional candidate genes associated with CFS . In addition, mice with mutations in several genes have shown phenotypes consistent with fatigue (eg, corticosteroid‐binding globulin ( Cbg ), recombinase activating gene 2 ( Rag2 ) and interleukin‐10 ( Il10 )) …”

“…[25][26][27][28][29][30][31] Furthermore, a recent study comparing CFS patients to healthy controls identified 442 additional candidate genes associated with CFS. 32 In addition, mice with mutations in several genes have shown phenotypes consistent with fatigue (eg, corticosteroidbinding globulin (Cbg), recombinase activating gene 2 (Rag2) and interleukin-10 (Il10)). [33][34][35] Random mutagenesis paired with forward genetic screening has been an indispensable tool for establishing and expanding our understanding of gene function in an unbiased manner.…”

Asleep at the Wheel: Forward Genetic ENU Mutagenesis Screen for Mouse Models of Chronic Fatigue Identifies a Mutation inSlc2a4(GLUT4)

“…3; group C, member 1 glucocorticoid receptor (NR3C1), and the glutamate receptor -69 ionotropic kinase 2 (GRIK2)) have been linked to both the occurrence and severity of 70 fatigue symptomology (24)(25)(26)(27)(28)(29)(30). A study comparing chronic fatigue syndrome patients to 71 healthy controls using a single nucleotide polymorphism (SNP) chip with over 900, 000 72 SNPs identified 442 candidates associated with chronic fatigue syndrome, and 73 highlighted two genes never before associated with fatigue (C-type lectin domain family 74 4, member M (CLEC4M) and coiled-coil domain containing 157 protein (CCDC157)) 75 (31). In addition, mice with mutations in several genes have shown phenotypes 76 consistent with fatigue (e.g., corticosteroid-binding globulin (CBG), recombinase 77 activating gene 2 (RAG2), and interleukin-10 (IL-10)) (32)(33)(34).…”