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.

Figure 1

Manhattan plot of genome-wide association raw P-values. The black (lower) horizontal line corresponds to the false discovery rate threshold of 3.3 × 10⁻⁵ and the grey horizontal line corresponds to the Bonferroni threshold of 7.5 × 10⁻⁸.

Figure 2

A genotypic organization of 38 controls (first 38 columns) and 42 ME/CFS cases (last 42 columns) on chromosome 6 between 136 172 610 and 136 647 610, containing the MAP7 gene. This region contains six SNPs found to be statistically significantly associated with the ME/CFS cohort. Four of these SNPs lie in the MAP7 region. The first seven cases show a genotypic pattern not shared by the control cohort: the red cells represent the homozygous genotype of the minor allele. The color bar directly to the left of the heatmap shows the intragenic and near-gene natures of most of the SNPs in the region. ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome.

Figure 3

A genotypic organization of 38 controls (first 38 columns) and 42 ME/CFS cases (last 42 columns) on chromosome 10 between 32 437 590 and 32 857 600. The genotypic pattern shared by the 16 ME/CFS cases at the right of the second panel occurs in only one of the controls. ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome.

Figure 4

A genotypic organization of 38 controls (first 38 columns) and 42 ME/CFS cases (last 42 columns) on chromosome 14 between 22 144 961 and 22 195 061 in a region containing the TCA (T-cell receptor alpha) gene and the SNP rs17255510 that is statistically significantly associated with our ME/CFS cohort. There is a distinct genotypic pattern shared by the last five ME/CFS cases. ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome.