Fine mapping of the major histocompatibility complex (MHC) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggests involvement of both HLA class I and class II loci

Hajdarevic, Riad; Lande, Asgeir; Rekeland, Ingrid Gurvin; Rydland, Anne; Strand, Elin Bolle; Sosa, Daysi Duarte; Creary, Lisa E.; Mella, Olav; Egeland, Torstein; Saugstad, Ola Didrik; Fluge, Øystein; Lie, Benedicte A.; Viken, Marte K.

doi:10.1016/j.bbi.2021.08.219

Cited by 8 publications

(8 citation statements)

References 36 publications

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“…In previous studies, this neglect does not seem problematic because estimated genotype error rates are below 1% (43). However, higher genotype error rates can be obtained for rare genetic markers (44), and genetic markers with minor allele frequencies less than 0.01 or 0.05 are typically excluded from genetic association studies of ME/CFS (22, 32, 45). The parameterization of our simulation study (i.e., θ 0 > 0.05) is then in line with this research practice and, thus, the respective findings are directly applicable for understanding the reproducibility of current genetic association studies of ME/CFS.…”

Section: Discussionmentioning

confidence: 99%

Impact of imperfect diagnosis in ME/CFS association studies

Malato

Graça

Sepúlveda

2022

Preprint

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The absence of an objective disease biomarker puts studies of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) under the curse of imperfect diagnosis. This problem leads to frequent reports that fail to reproduce prior published studies. To address the impact of imperfect diagnosis on the robustness of studies’ conclusions, we conducted a simulation study to quantify the statistical power to detect a disease association with a hypothetical binary factor in the presence of imperfect diagnosis. Using the classical case-control design, studies with sample sizes of less than 500 individuals per group could not reach the target power of at least 80% to detect realistic disease associations. We then recreated serological association studies in which the chance of imperfect diagnosis was combined with the probability of misclassifying a binary factor, as it happens in a typical serological association study. In this case, the target power of 80% could only be achieved for studies with more than 1000 individuals per group. Given the current sample sizes of ME/CFS studies, our results suggest that most studies are likely to be underpowered due to imperfect diagnosis alone. To increase reproducibility across studies, we provided some practical recommendations, such as the use of standard case definitions together with multi-centric study designs, and routine reporting of power calculations under a non-negligible chance of misdiagnosis. Our results can also inform the design of future studies under the assumption of misdiagnosis.

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Section: Discussionmentioning

confidence: 99%

Impact of imperfect diagnosis in ME/CFS association studies

Malato

Graça

Sepúlveda

2022

Preprint

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“…Genotyping data for 27 SNPs in the TRA locus (chr14:21,870,000-23,500,000; GRChr37) were extracted for the cases and controls from previously genotyped array datasets [ 21 , 23 , 24 ], generated using Infinium ImmunoArray-24 v2 BeadChip and HumanImmuno-v1 BeadChip (Illumina, San Diego, USA). In addition, three SNPs, not present in the array dataset, were genotyped using Taqman SNP Genotyping Assays (Thermo Fisher Scientific, Waltham, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…The gender distribution was 336 females (82%) and 73 males (18%) in ME/CFS patients, and 448 females (55%) and 362 males (45%) in controls. All patients have previously been included in association studies of the HLA region and have given informed consent [13,21], however, only patients with DNA currently available were included in this study. The research project was approved by the Regional Committees for Medical and Health Research Ethics (REK, 2015/1547).…”

Section: Materials and Methods Study Populationmentioning

confidence: 99%

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No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

et al. 2022

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants. We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value <5 × 10−8). As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls). We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510. No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts. However, other SNPs showed signs of association (P value <0.05) in the UK Biobank cohort and meta-analyses of Norwegian and UK biobank cohorts, but none survived correction for multiple testing. Hence, our research did not identify any reliable associations with variants in the TRA locus.

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“…187 Many other studies found a significant association between ME/CFS and polymorphisms in the disrupted-in-schizophrenia 1 gene (DISC1), with copy number variants in genes associated with the function of the central nervous system, as well as with polymorphisms in ion channels and acetylcholine receptors, as well as with previously mentioned polymorphisms in HLA class I and class II loci. [188][189][190][191] One more study examined the contribution of AMPD1, CPT2, and PGYM genes, but no significant association was detected with CFS. 192 In addition, polymorphisms in neuroendocrine effector and receptor genes like TPH2, COMT, and NR3C1 were found to predict the development of CFS.…”

Section: Findings From Genetic Association and Cohort Studies Of Me/cfsmentioning

confidence: 99%

Genetics of COVID‐19 and myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review

Tziastoudi

Cholevas

Stefanidis

et al. 2022

Ann Clin Transl Neurol

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COVID‐19 and ME/CFS present with some similar symptoms, especially physical and mental fatigue. In order to understand the basis of these similarities and the possibility of underlying common genetic components, we performed a systematic review of all published genetic association and cohort studies regarding COVID‐19 and ME/CFS and extracted the genes along with the genetic variants investigated. We then performed gene ontology and pathway analysis of those genes that gave significant results in the individual studies to yield functional annotations of the studied genes using protein analysis through evolutionary relationships (PANTHER) VERSION 17.0 software. Finally, we identified the common genetic components of these two conditions. Seventy‐one studies for COVID‐19 and 26 studies for ME/CFS were included in the systematic review in which the expression of 97 genes for COVID‐19 and 429 genes for ME/CFS were significantly affected. We found that ACE, HLA‐A, HLA‐C, HLA‐DQA1, HLA‐DRB1, and TYK2 are the common genes that gave significant results. The findings of the pathway analysis highlight the contribution of inflammation mediated by chemokine and cytokine signaling pathways, and the T cell activation and Toll receptor signaling pathways. Protein class analysis revealed the contribution of defense/immunity proteins, as well as protein‐modifying enzymes. Our results suggest that the pathogenesis of both syndromes could involve some immune dysfunction.

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Fine mapping of the major histocompatibility complex (MHC) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggests involvement of both HLA class I and class II loci

Cited by 8 publications

References 36 publications

Impact of imperfect diagnosis in ME/CFS association studies

Impact of imperfect diagnosis in ME/CFS association studies

No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Genetics of COVID‐19 and myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review

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