Immune dysfunction contributes to comorbid depression in patients with multiple sclerosis.

Background: Epstein-Barr virus (EBV), a common human lymphotropic herpes virus infecting over 95% of the overall individuals. Strong evidence from recent research that EBV is a contributing factor in multiple sclerosis (MS). The exact mechanism by which EBV might exacerbate MS in risk groups is unknown. Objectives: To determine plasma levels of Autophagy-related proteins 5 (ATG5) and Epstein-Barr virus nuclear antigen1 (EBNA1) IgG. Additionally, assessing EBV DNA load in MS patients in relation to disease activity. Also, studying the relation between EBV DNA burden and the plasma levels of ATG5 and EBNA1 IgG in MS patients. Methodology: The study was conducted on 23 relapsing remitting MS (RRMS) patients in active attack, 23 RRMS patients' in-between attacks and 23 healthy controls. Enzyme-linked immunosorbent assay (ELISA) method was used to measure the amount of ATG5 and EBNA1 IgG in plasma. Real-time polymerase chain reaction (real-time PCR) was used to assess the EBV DNA load in peripheral blood mononuclear cells (PBMCs). Results: No statistically significant difference in ATG5 or EBNA1 IgG level between MS patients and healthy controls. However, all MS patients (100%) were EBNA1 IgG positive while 91.3% of the control group were EBNA1 IgG positive. EBV DNA load did not show statistically significant difference between MS patients and healthy controls. Significant positive correlation between EBV DNA load and ATG5 plasma level in MS patients in between attacks, P value =0.019. Conclusion: ATG5 levels and EBV DNA load could be utilized to predict disease-related activities in predisposed individuals or MS patients.

Individuals with posttraumatic stress disorder (PTSD) are significantly more likely to be diagnosed with cardiovascular disease (CVD) (e.g., myocardial infarction, stroke). The evidence for this link is so compelling that the National Institutes of Health convened a working group to determine gaps in the literature, including the need for large-scale genomic studies to identify shared genetic risk. The aim of the present study was to address some of these gaps by utilizing PTSD and CVD genome-wide association study (GWAS) summary statistics in a large biobank sample to determine the shared genetic risk of PTSD and CVD. A large health care biobank data set was used (N=36,412), combined with GWAS summary statistics from publicly available large-scale PTSD and CVD studies. Disease phenotypes (e.g., PTSD) were collected from electronic health records. De-identified genetic data from the biobank were genotyped using Illumina SNP array. Summary statistics data sets were processed with the following quality-control criteria: 1) SNP heritability h2 >0.05, 2) compute z-statistics (z=beta/SE or z=log(OR)/SE), 3) filter nonvariable SNPs (0<freq<1), and 4) filter SNPs with low number of samples. The multitrait analysis of GWAS (MTAG) approach was used to combine GWAS summary statistics. Significant genetic correlations were found between PTSD and CVD (rG=0.24, SE=0.06), and Mendelian randomization analyses indicated a potential causal link from PTSD to hypertension (β=0.20, SE=0.04), but not the reverse. PTSD summary statistics significantly predicted PTSD diagnostic status (R2=0.27), and this was significantly improved by incorporating summary statistics from CVD and major depressive disorder (R2=1.30). Further, pathway enrichment analyses indicated that genetic variants involved in shared PTSD-CVD risk included those involved in postsynaptic structure, synapse organization, and interleukin-7-mediated signaling pathways. The results from this study suggest that PTSD and CVD may share genetic risk. Further, these results implicate PTSD as a risk factor leading to the development of hypertension and coronary artery disease. Additional research is needed to determine the clinical utility of these findings.

BackgroundObservational studies have suggested an association between multiple sclerosis (MS) and cortical structure, but the results have been inconsistent.ObjectiveWe used two-sample Mendelian randomization (MR) to assess the causal relationship between MS and cortical structure.MethodsMS data as the exposure trait, including 14,498 cases and 24,091 controls, were obtained from the International Multiple Sclerosis Genetics Consortium. Genome-wide association study (GWAS) data for cortical surface area (SAw/nw) and thickness (THw/nw) in 51,665 individuals of European ancestry were obtained from the ENIGMA Consortium. The inverse-variance weighted (IVW) method was used as the primary analysis for MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Enrichment analysis was performed on MR analyses filtered by sensitivity analysis.ResultsAfter IVW and sensitivity analysis filtering, only six surviving MR results provided suggestive evidence supporting a causal relationship between MS and cortical structure, including lingual SAw (p = .0342, beta (se) = 5.7127 (2.6969)), parahippocampal SAw (p = .0224, beta (se) = 1.5577 (0.6822)), rostral middle frontal SAw (p = .0154, beta (se) = − 9.0301 (3.7281)), cuneus THw (p = .0418, beta (se) = − 0.0020 (0.0010)), lateral orbitofrontal THw (p = .0281, beta (se) = 0.0025 (0.0010)), and lateral orbitofrontal THnw (p = .0417, beta (se) = 0.0029 (0.0014)). Enrichment analysis suggested that leukocyte cell-related pathways, JAK-STAT signaling pathway, NF-kappa B signaling pathway, cytokine-cytokine receptor interaction, and prolactin signaling pathway may be involved in the effect of MS on cortical morphology.ConclusionOur results provide evidence supporting a causal relationship between MS and cortical structure. Enrichment analysis suggests that the pathways mediating brain morphology abnormalities in MS patients are mainly related to immune and inflammation-driven pathways.

Study aimed to investigate the genetic correlations and potential causal relationships between obstructive sleep apnoea (OSA) and various cardiovascular diseases (CVDs), aiming to enhance understanding of shared genetic mechanisms and improve recognition and treatment of OSA in patients with CVDs. Utilizing genome-wide association study (GWAS) data, we analysed shared genetics between OSA and CVDs using linkage disequilibrium score regression, multi-trait analysis of GWAS (MTAG), and genotype-tissue expression analysis. We further investigated causal relationships using Bayesian co-localization tests, bidirectional Mendelian randomization, and latent causal variable analysis. We found strong associations between OSA and multiple CVDs: coronary artery disease (CAD), heart failure (HF), myocardial infarction (MI), stroke, and atrial fibrillation (AF). Novel single-nucleotide polymorphisms related to CVDs were identified during single-trait MTAG analysis. By applying cross-trait MTAG, we identified 15 shared loci between OSA and CAD, 25 shared loci between OSA and MI, and 7 shared loci between OSA and HF. Shared genes are primarily expressed in the blood, heart, kidney, liver, muscle, and pancreas. Mendelian randomization analysis indicated a significant causal effect of OSA on HF and AF as a causal factor for OSA. Latent causal variable analysis suggested that AF was causally associated with OSA, while HF showed partial causality. Our study suggests strong genetic correlations between OSA and several CVDs. Further research is needed on the associations between OSA and CVDs, as well as the mechanisms of the identified loci. This study explores the genetic links between obstructive sleep apnoea (OSA) and cardiovascular diseases (CVDs).Key findings are as follows:Strong genetic correlations were found between OSA and five CVDs: coronary artery disease, heart failure (HF), myocardial infarction, stroke, and atrial fibrillation. Novel correlated and causal loci were identified.Atrial fibrillation was identified as a causal factor for OSA, while OSA was a causal factor for HF.Future research is needed to explore these genetic mechanisms further and improve understanding of the connections between OSA and CVDs.

BackgroundNationwide surveys conducted in Japan over the past thirty years have revealed a four-fold increase in the estimated number of multiple sclerosis (MS) patients, a decrease in the age at onset, and successive increases in patients with conventional MS, which shows an involvement of multiple sites in the central nervous system, including the cerebrum and cerebellum. We aimed to clarify whether genetic and infectious backgrounds correlate to distinct disease phenotypes of MS in Japanese patients.Methodology/Principal FindingsWe analyzed HLA-DRB1 and -DPB1 alleles, and IgG antibodies specific for Helicobacter pylori, Chlamydia pneumoniae, varicella zoster virus, and Epstein-Barr virus nuclear antigen (EBNA) in 145 MS patients and 367 healthy controls (HCs). Frequencies of DRB1*0405 and DPB1*0301 were significantly higher, and DRB1*0901 and DPB1*0401 significantly lower, in MS patients as compared with HCs. MS patients with DRB1*0405 had a significantly earlier age of onset and lower Progression Index than patients without this allele. The proportion and absolute number of patients with DRB1*0405 successively increased with advancing year of birth. In MS patients without DRB1*0405, the frequency of the DRB1*1501 allele was significantly higher, while the DRB1*0901 allele was significantly lower, compared with HCs. Furthermore, DRB1*0405-negative MS patients were significantly more likely to be positive for EBNA antibodies compared with HCs.ConclusionsOur study suggests that MS patients harboring DRB1*0405, a genetic risk factor for MS in the Japanese population, have a younger age at onset and a relatively benign disease course, while DRB1*0405-negative MS patients have features similar to Western-type MS in terms of association with Epstein-Barr virus infection and DRB1*1501. The recent increase of MS in young Japanese people may be caused, in part, by an increase in DRB1*0405-positive MS patients.

BackgroundMultiple sclerosis (MS) is a neurological disease that is caused by an autoimmune response that results in the neuron’s demyelination in the central nervous system. The exact etiology of MS is not clear; however, several environmental and genetic factors are believed to participate in its initiation and development, including exposure to viruses. This study aims to investigate the association between the seropositivity and antibody titer of selected herpesviruses and MS in Jordanian MS patients.MethodIn this study, 55 MS patients and 40 age- and gender-matching apparently healthy volunteers were recruited from two main hospitals in the north of Jordan. MS patients were grouped into three types of MS based on the clinical presentation of the disease. Blood samples were collected from the participants and the IgG antibodies for human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV) nuclear antigen (EBNA), EBV viral capsid antigen (VCA) and varicella-zoster virus (VZV) were assayed by ELISA. The prevalence of seropositivity and the antibody level for each of the antibodies were compared between MS patients and controls and between the three types of MS.ResultsThere was no significant difference in the prevalence of seropositivity and in the levels of antibodies for HHV-6, EBNA and VCA between MS patients and controls and between the three types of MS. In contrast, the number of seropositive patients and the level of IgG antibodies for VZV were significantly higher in MS patients compared to the control.ConclusionThis study showed that patients with MS in the north of Jordan were more likely to be seropositive for VZV than the general population. Based on this finding, we recommend further studies to evaluate the seropositivity to VZV to be carried out in other parts of Jordan and the greater middle east to find out if there is a correlation between MS and previous infection with VZV.

BackgroundPosttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). MethodsA GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. ResultsGWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. ConclusionsThrough using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

Background and ObjectivesDecreased vitamin D levels and obesity are associated with an increased risk for multiple sclerosis (MS). However, whether they also affect the disease course after onset remains unclear. With larger data sets now available, we used Mendelian randomization (MR) to determine whether serum 25-hydroxyvitamin D (25OHD) and body mass index (BMI) are causally associated with MS risk and, moving beyond susceptibility toward heterogeneity, with relapse hazard.MethodsWe used genetic variants from 4 distinct genome-wide association studies (GWASs) for serum 25OHD in up to 416,247 individuals and for BMI from a GWAS in 681,275 individuals. Applying 2-sample MR, we examined associations of 25OHD and BMI with the risk of MS, with summary statistics from the International Multiple Sclerosis Genetics Consortium GWAS in 14,802 MS cases and 26,703 controls. In addition, we examined associations with relapse hazard, with data from our GWAS in 506 MS cases.ResultsA 1-SD increase in genetically predicted natural-log transformed 25OHD levels decreased odds of MS up to 28% (95% CI: 12%–40%, p = 0.001) and decreased hazard for a relapse occurring up to 43% (95% CI: 15%–61%, p = 0.006). A 1-SD increase in genetically predicted BMI, corresponding to roughly 5 kg/m2, increased risk for MS with 30% (95% CI: 15%–47%, p = 3.76 × 10−5). On the contrary, we did not find evidence for a causal role of higher BMI with an increased hazard for occurrence of a relapse.DiscussionThis study supports causal effects of genetically predicted serum 25OHD concentrations and BMI on risk of MS. In contrast, serum 25OHD but not BMI is significantly associated with relapse hazard after onset. These findings might offer clinical implications for both prevention and treatment.

Genome-wide association studies (GWAS) have identified numerous genetic loci associated with mineral metabolism markers but have exclusively focused on single-trait analysis. In this study, we performed a multi-trait analysis of GWAS (MTAG) of mineral metabolism, exploring overlapping genetic architecture between traits to identify novel genetic associations for fibroblast growth factor 23 (FGF23). We applied MTAG to variants common to GWAS of 5 genetically correlated mineral metabolism markers in European-ancestry participants. We integrated UK BioBank GWAS for blood levels for phosphate, 25-hydroxyvitamin D, and calcium (n=366,484) and CHARGE GWAS for parathyroid hormone (n=29,155) and FGF23 (n=13,716). We then used supervised and unsupervised deep machine learning to identify novel associations between genetic traits and FGF23. MTAG increased the effective sample size for mineral metabolism markers to n=50,325 for FGF23. After clumping, MTAG identified independent genome-wide significant SNPs for all traits, including 62 loci for FGF23. Many of these loci have not been previously reported in single-trait analyses. Through a functional genomics approach, we identified Histidine-rich glycoprotein (HRG) and high-mobility-group-box 1 (HMGB1) as master regulators of downstream canonical pathways associated with circulating FGF23, and both genes were highly enriched in hypertrophied cardiac tissue of deceased hemodialysis patients. In addition, we found DNMT3A was associated with uremic toxin, 8-Hydroxy-2-deoxyguanosine, a biomarker of DNA damage. In silico gene perturbation analysis revealed DNMT3A is protective in patients with heart failure caused by hypertrophied or dilated cardiomyopathy. Our findings highlight the importance of MTAG analysis of mineral metabolism markers to boost the number of genome-wide significant loci for FGF23 to identify novel genetic traits. Functional genomics revealed novel networks that inform unique cellular functions and identified HRG-HMGB1 as key master regulators of FGF23 and cardiovascular disease in CKD.

Genome-wide association studies (GWASs) revealed that variants of STAT3 are associated with multiple sclerosis (MS) risk. There are several studies showing the effect of ethnicity and genetic background on the characteristics of MS. Here, we aimed to investigate STAT3 gene expression status along with its two regulatory long non-coding RNAs, lnc-DC and THRIL, in order to compare the expression of these target genes among two different ethnicities in the east of Iran. A case-control study was performed between two groups of MS populations in east of Iran. We recruited individuals with Kurdish ethnicity from North Khorasan and Sistani ethnicity from southeast of Iran. The peripheral blood mononuclear cells were obtained from all participants, and total RNA was extracted. The gene expression of the selected genes was evaluated by qPCR. The expression of THRIL in North Khorasan MS patients was significantly higher than controls (P = 0.03). The results of simultaneous analysis of expression of the target genes (STAT3, THRIL, and lnc-DC) in both ethnic groups failed to show any significant difference between the MS patients and controls (P > 0.05). In addition, the expression of STAT3 and THRIL genes in Sistani MS patients was statistically meaningful lower than healthy controls (P < 0.05). To our knowledge, this is the first study that compared the expression of the STAT3 gene and its regulatory molecules between two ethnic groups of Iranian MS patients. We suggested that STAT3 and its associated molecules might be differentially expressed and regulated in MS patients with different genetic background.

Multi-Trait Genetic Analysis Identifies Autoimmune Loci Associated with Cutaneous Melanoma

Over the past years, genome-wide association studies (GWAS) have generated a wealth of new information. Summary data from many GWAS are now publicly available, promoting the development of many statistical methods for association studies based on GWAS summary statistics, which avoids the increasing challenges associated with individual-level genotype and phenotype data sharing. However, for population-based association studies such as GWAS, it has been long recognized that population stratification can seriously confound association results. For large GWAS, it is very likely that there exist population stratification and cryptic relatedness, which will result in inflated Type I error in association testing. Although many methods have been developed to control for population stratification, only two of these approaches can be used to control population stratification without individual-level data: one is based on genomic control (GC) and the other one is based on linkage disequilibrium score regression (LDSC). However, the performance of these two approaches is currently unknown. In this study, we use extensive simulation studies including populations with subpopulations, spatially structured populations, and populations with cryptic relatedness to compare the performance of these two approaches to control for population stratification using only GWAS summary statistics without individual-level data. Data sets from the genetic analysis workshop 19and UK Biobank are also used to evaluate these two approaches. We demonstrate that the intercept of LDSC can be used as a more accurate correction factor than GC. The results from this study will provide very useful information for researchers using GWAS summary statistics while trying to control for population stratification.

Bone marrow cells in patients with multiple sclerosis

Autoreactive T-Cell Responses in Primary Biliary Cirrhosis Are Proinflammatory Whereas Those of Controls Are Regulatory

Cytokines, including tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6), have been implicated in the pathogenesis of multiple sclerosis (MS). The production and release of these cytokines are regulated in part by specific purinergic (adenosine) cell surface receptors. To determine the extent to which the adenosine A1 receptor influenced cytokine expression in peripheral blood mononuclear cells (PBMCs) from MS and control patients, we measured plasma adenosine and TNF alpha levels, A1 receptor messenger RNA (mRNA) and protein amounts, and the effects of activation of A1 receptors on TNF alpha and IL-6 production by PBMCs. Plasma levels of TNF alpha were significantly higher and adenosine levels were significantly lower in MS patients compared with control subjects. Levels of TNF alpha and IL-6 in mitogen-stimulated PBMC culture supernatants from MS patients or control patients were similar. Conversely, treatment of PBMCs with the adenosine A1 receptor agonist R-phenylisopropyladenosine (R-PIA) (1 microM) significantly inhibited mitogen-stimulated production of TNF alpha but not IL-6 in control subjects and significantly inhibited production of IL-6 but not TNF alpha in MS patients. The effects of R-PIA were selectively blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). A1 receptor protein levels were decreased significantly in PBMCs from MS patients. Taken together, these results suggest that decreased levels of adenosine and its A1 receptor modulate TNF alpha and IL-6 levels and may contribute to the pathogenesis of MS.