Research 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 9 06 600 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-valueo0.05). 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.
INTRODUCTION
Myalgic encephalomyelitis, also known as chronic fatigue syndrome or ME/CFS, is a complex and heterogeneous disease that has a severe impact on the health and quality of life of those afflicted.
Current estimates suggest that as many as 2.5% of adults may suffer from ME/CFS.1,2
The etiology of ME/CFS is currently unknown; however, it is often characterized by neurological symptoms, memory and concentration impairment, viral reactivation and sleep abnormalities.3
Inflammatory sequelae and innate immune dysregulation are also commonly reported and include increased proinflammatory cytokine expression and decreased natural killer cell function and numbers, potentially leading to increased susceptibility to infection.4–6
In addition, ME/CFS cases often present with gastrointestinal abnormalities, which are commonly misdiagnosed initially as irritable bowel syndrome.7–11
Currently, there is no pathognomonic biomarker or clinical diagnostic test that can definitively delineate ME/CFS; therefore, diagnosis is mainly based on clinical observation and medical anamnesis with subjects meeting defined inclusion and exclusion criteria.12,13
Several lines of evidence support the possibility that ME/CFS development may involve a heritable component. Albright et al.14 conducted familial clustering analysis and reported
significantly higher risk for ME/CFS for first-degree relatives.
In addition, studies of monozygotic and dizygotic twins suggest that there is a higher rate of fatigue concordance in monozygotic twins when compared with dizygotic twins.15,16
The expression of major histocompatibility complex class II antigens HLA-DQA1*01 and HLA-DR4 has also been suggested as a potential risk factor in developing ME/CFS.17,18
Moreover, single-nucleotide polymorphisms (SNPs) in the tumor necrosis factor-a and interferon-y genes may implicate genetic factors in the dysregulation of inflammatory cytokine production.19
In recent years, genome-wide association studies (GWAS) have brought exciting new insights into the genetic underpinnings of many complex diseases.
Polymorphisms have been identified in genes coding for proteins implicated in the disease processes of multiple sclerosis,20 systemic lupus erythematosus21 and Alzheimer’s disease.22
In addition, GWAS have proven to be instrumental in identifying genes with complex interactions.23–25
Current SNP arrays allow for the concurrent screening of approximately one million known human SNPs, a capacity that has contributed notably to our knowledge of genetic influences on disease pathology.26
Previous to this study, only one single large (41 00 000 SNPs) GWAS has been conducted to address the pathophysiology of ME/CFS.27
Smith et al. genotyped 40 ME/CFS subjects meeting the 1994 Fukuda et al. criteria13 and 40 controls with 1 16 204 known SNPs.
Three polymorphisms of interest were highlighted: two SNPs in GRIK2, a gene implicated in a number of neurological maladies such as autism and schizophrenia and an SNP within the NPAS2 gene, which is a putative circadian clock gene.
By screening ME/CFS cases and controls, we identified 442 candidate SNPs that associated with the disease cohort with statistical significance.
Our pilot study supports the previous observations of other genetic screening studies and extends these results by identifying additional potential candidate polymorphisms.
Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome, by KA Schlauch, SF Khaiboullina, KL De Meirleir, S Rawat, J Petereit, AA Rizvanov, N Blatt, T Mijatovic, D Kulick, A Palotás and VC Lombardi in Translational Psychiatry (2016) 6, e730 [published online 9 Feb 2016]
