Quantitative susceptibility mapping (QSM) and R2* relaxation rate mapping have demonstrated increased iron deposition in the substantia nigra of patients with idiopathic Parkinson's disease (PD). However, the findings in other subcortical deep gray matter nuclei are converse and the sensitivity of QSM and R2* for morphological changes and their relation to clinical measures of disease severity has so far been investigated only sparsely.

Genetic epidemiology studies have established that the natural variation of gene expression profiles is heritable and has genetic bases. A number of proximal and remote DNA variations, known as expression quantitative trait loci (eQTLs), that are associated with the expression phenotypes have been identified, first in Epstein-Barr virus-transformed lymphoblastoid cell lines and later expanded to other cell and tissue types. Integration of the eQTL information and the network analysis of transcription modules may lead to a better understanding of gene expression regulation. As these network modules have relevance to biological or disease pathways, these findings may be useful in predicting disease susceptibility.

Pathogenic variants in cancer susceptibility genes can increase the risk of a spectrum of diseases, which clinicians must manage for their patients. We evaluated the disease spectrum of breast cancer susceptibility genes (BCSGs) with the aim of developing a comprehensive resource of gene-disease associations for clinicians.

Chronic wasting disease (CWD) is a contagious, fatal, neurodegenerative prion disease of cervids. The expanding geographical range and rising prevalence of CWD are increasing the risk of pathogen transfer and spillover of CWD to non-cervid sympatric species. As beavers have close contact with environmental and food sources of CWD infectivity, we hypothesized that they may be susceptible to CWD prions. We evaluated the susceptibility of beavers to prion diseases by challenging transgenic mice expressing beaver prion protein (tgBeaver) with five strains of CWD, four isolates of rodent-adapted prions and one strain of Creutzfeldt-Jakob disease. All CWD strains transmitted to the tgBeaver mice, with attack rates highest from moose CWD and the 116AG and H95+ strains of deer CWD. Mouse-, rat-, and especially hamster-adapted prions were also transmitted with complete attack rates and short incubation periods. We conclude that the beaver prion protein is an excellent substrate for sustaining prion replication and that beavers are at risk for CWD pathogen transfer and spillover.

Th17 cells are known to be involved in several autoimmune or inflammatory diseases. In celiac disease (CD), recent studies suggest an implication of those cells in disease pathogenesis. We aimed at studying the role of genes relevant for the Th17 immune response in CD susceptibility. A total of 101 single nucleotide polymorphisms (SNPs), mainly selected to cover most of the variability present in 16 Th17-related genes (IL23R, RORC, IL6R, IL17A, IL17F, CCR6, IL6, JAK2, TNFSF15, IL23A, IL22, STAT3, TBX21, SOCS3, IL12RB1 and IL17RA), were genotyped in 735 CD patients and 549 ethnically matched healthy controls. Case-control comparisons for each SNP and for the haplotypes resulting from the SNPs studied in each gene were performed using chi-square tests. Gene-gene interactions were also evaluated following different methodological approaches. No significant results emerged after performing the appropriate statistical corrections. Our results seem to discard a relevant role of Th17 cells on CD risk.

Coronary artery disease (CAD) is the principal cause of death in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to investigate whether NAFLD is causally involved in the pathogenesis of CAD. For this, previously reported NAFLD susceptibility genes were clustered and tested for an association with CAD in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) Consortium data set. The role of plasma lipids as a potential mediator was explored by using data from the Global Lipids Genetics Consortium. Statistical analyses revealed that the combination of 12 NAFLD genes was not associated with CAD in 60,801 CAD cases and 123,504 controls (odds ratio [OR] per NAFLD risk allele, 1.0; 95% confidence interval [CI], 0.99-1.00). In a subsequent sensitivity analysis, a positive relationship was observed after exclusion of gene variants that are implicated in NAFLD through impaired very low-density lipoprotein secretion (i.e., microsomal triglyceride transfer protein [MTTP], patatin-like phospholipase domain containing 3 [PNPLA3], phosphatidylethanolamine N-methyltransferase [PEMT], and transmembrane 6 superfamily member 2 [TM6SF2]) (OR, 1.01; 95% CI, 1.00-1.02). Clustering of the excluded genes showed a significant negative relationship with CAD (OR, 0.97; 95% CI, 0.96-0.99). A substantial proportion of the observed heterogeneity between the individual NAFLD genes in relation to CAD could be explained by plasma lipids, as reflected by a strong relationship between plasma lipids and CAD risk conferred by the NAFLD susceptibility genes (r = 0.76; P = 0.004 for low-density lipoprotein cholesterol). Conclusion: NAFLD susceptibility genes do not cause CAD per se. The relationship between these genes and CAD appears to depend to a large extent on plasma lipids. These observations strongly suggest taking plasma lipids into account when designing a new drug to target NAFLD.

Cognitive problems have been reported in breast cancer patients after chemotherapy. A small group of older breast cancer survivors carrying the APOE4 gene, receiving chemotherapy, was at increased risk of long-term impairment of brain function. We have analyzed the expression of APOE and the next 23-ranked Alzheimer's disease (AD) susceptibility genes in malignant breast tumors. We wished to determine if these 24 genes might be related to breast cancer.

Tuberculosis remains a major health problem in developing countries especially with the emergence of multidrug resistant strains. Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare disorder with impaired immunity against mycobacterial pathogens. Reported MSMD etiologies highlight the crucial role of the Interferon gamma /Interleukin 12 (IFN-γ/ IL-12) axis and the phagocyte respiratory burst axis.

The gene family of serine protease inhibitors of the Kazal type (SPINK) are functional and positional candidate genes for celiac disease (CD). Our aim was to assess the gut mucosal gene expression and genetic association of SPINK1, -2, -4, and -5 in the Dutch CD population. Gene expression was determined for all four SPINK genes by quantitative reverse-transcription polymerase chain reaction in duodenal biopsy samples from untreated (n=15) and diet-treated patients (n=31) and controls (n=16). Genetic association of the four SPINK genes was tested within a total of 18 haplotype tagging SNPs, one coding SNP, 310 patients, and 180 controls. The SPINK4 study cohort was further expanded to include 479 CD cases and 540 controls. SPINK4 DNA sequence analysis was performed on six members of a multigeneration CD family to detect possible point mutations or deletions. SPINK4 showed differential gene expression, which was at its highest in untreated patients and dropped sharply upon commencement of a gluten-free diet. Genetic association tests for all four SPINK genes were negative, including SPINK4 in the extended case/control cohort. No SPINK4 mutations or deletions were observed in the multigeneration CD family with linkage to chromosome 9p21-13 nor was the coding SNP disease-specific. SPINK4 exhibits CD pathology-related differential gene expression, likely derived from altered goblet cell activity. All of the four SPINK genes tested do not contribute to the genetic risk for CD in the Dutch population.

Identification of inflammatory bowel disease (IBD) susceptibility genes is key to understanding pathogenic mechanisms. Recently, the North American IBD Genetics Consortium provided compelling evidence for an association between ileal Crohn's disease (CD) and the IL23R gene using genome-wide association scanning. External replication is a priority, both to confirm this finding in other populations and to validate this new technique. We tested for association between IL23R and IBD in a large independent UK panel to determine the size of the effect and explore subphenotype correlation and interaction with CARD15.

Kawasaki disease (KD) is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209) in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD.

The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds (PT) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing (PEMP2 ≤ 0.05). The TLR7/TLR8 locus was associated with disease onset before and the SH2B3/ATXN2, ITGA4/UBE2E3 and IL2/IL21 loci after 7 years of age. The latter three loci were associated with a more severe small bowel mucosal damage and SH2B3/ATXN2 with type 1 diabetes. Patients at the highest wGRS39 tertiles had OR > 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis (PT = 0.2, PEMP2 = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.

This study explores the magnetostatic properties of the Alzheimer's disease brain using a recently proposed, magnetic resonance imaging, postprocessed contrast mechanism. Quantitative susceptibility mapping (QSM) has the potential to monitor in vivo iron levels by reconstructing magnetic susceptibility sources from field perturbations. However, with phase data acquired at a single head orientation, the technique relies on several theoretical approximations and requires fast-evolving regularisation strategies.

Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control.

Patients with Parkinson's disease (PD) have elevated levels of brain iron, especially in the nigrostriatal dopaminergic system. The purpose of this study was to evaluate the iron deposition in the substantia nigra (SN) and other deep gray matter nuclei of PD patients using quantitative susceptibility mapping (QSM) and its clinical relationship, and to explore whether there is a gradient of iron deposition pattern in globus pallidus (GP)-fascicula nigrale (FN)-SN pathway.

Several recent genome-wide association studies (GWAS) identified susceptibility loci/genes for Behçet's disease (BD). However, no study has specifically investigated the genetic susceptibility loci associated with intestinal involvement in BD. We aimed to identify distinctive genetic susceptibility loci/genes associated with intestinal involvement in BD and determine their roles in intestinal inflammation as well as their interactions with genes involved in inflammatory bowel disease (IBD). GWAS and validation studies showed intestinal BD-specific associations with an NAALADL2 gene locus (rs3914501, P = 3.8 × 10-4) and a YIPF7 gene locus (rs6838327, P = 3.5 × 10-4). Validation, haplotype, and pathway analyses showed distinct genetic architectures between intestinal BD and BD without intestinal involvement. Furthermore, network analysis revealed shared pathogenic pathways between intestinal BD and IBD. Gene functional analyses indicated that down-regulation of NAALADL2 and YIPF7 expression was associated with exacerbating intestinal inflammatory responses both in vitro and in vivo. Our results provide new insights into intestinal BD-specific genetic variations, which represents a distinct pathway from BD without intestinal involvement. Functional consequences of the intestinal BD-specific NAALADL2 and YIPF7 expression patterns proved a suggestive association with intestinal inflammation risk, which warrants further validation.

We surveyed published papers and an international sickle cell disease (SCD) registry to detect susceptibility and clinical course of coronavirus disease 2019 (COVID-19) in SCD patients. COVID-19 presentation was mild in children and moderate in many SCD adults. Regarding increased comorbidities with age, it seems severe COVID-19 to be more common in older SCD patients. Although the overall outcome of COVID-19 was favorable in SCD children, a high rate of pediatric intensive care unit admission should be considered in managing these patients. To explain COVID-19 outcome in SCD patients, the possible benefits of hydroxyurea therapy could be considered. The obtained results should be interpreted, considering low cases from sub-Saharan people, younger age of SCD patients compared to general population, a bias toward registry of the more severe form of disease, the effect of pre-existing comorbidities with multisystem organ damage, and the role of health socio-economic determinants.

It has been reported that a single nucleotide polymorphism (SNP), rs2373115, in the GRB-associated binding protein 2 (GAB2) gene was associated with late-onset AD in Caucasians. Subsequently, other researchers have attempted to validate this finding in different ethnic populations. However, these findings have produced both negative and positive results. To derive a more precise estimation for whether GAB2 polymorphism rs2373115 is associated with sporadic Alzheimer's disease (SAD), we performed the present meta-analysis. Databases including PubMed, AlzGene, China National Knowledge Infrastructure (CNKI) and Wan Fang were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. All analyses were calculated using STATA Version 11.0 and RevMan (v.5.1) software. Ten total case-control studies were included. The statistical results showed that GAB2 SNP rs2373115 is significantly associated with an increased risk for SAD, and the subgroup analysis showed that SNP rs2373115 may only be associated with an increased risk for SAD risk in Caucasians but not in Asians. Furthermore, in APOE ɛ4 carriers or noncarriers, those with rs2373115 genotype GG did not have a significantly higher risk for SAD compared with those with genotype GT and TT (APOE ɛ4 carriers: OR=1.20, 95% CI=0.92-1.56, P=0.178; APOE ɛ4 noncarriers: OR=1.08, 95% CI=0.97-1.20, P=0.157) in the present study. The current meta-analysis further supports previous findings that the GAB2 gene may be associated with SAD risk.

Polycystic ovary syndrome (PCOS) is a complex disorder with heterogenous phenotypes and unclear etiology. A recent phenotypic clustering study identified metabolic and reproductive subtypes of PCOS. We hypothesize that the heterogeneity of PCOS manifestations reflects different mechanistic pathways and can be identified using a genetic approach. We applied k-means clustering to categorize the genome-wide significant PCOS variants into clusters based on their associations with selected quantitative traits that likely reflect PCOS etiological pathways. We evaluated the association of each cluster with PCOS-related traits and disease outcomes. We then applied Mendelian randomization to estimate the causal effects between the traits and PCOS. Three categories of variants were identified: adiposity, insulin resistant, and reproductive. Significant associations were observed for variants in the adiposity cluster with body mass index (BMI), waist circumference and breast cancer, and variants in the insulin-resistant cluster with fasting insulin, glucose values, and homeostatic model assessment of insulin resistance (HOMA-IR). Sex hormone binding globulin (SHBG) has strong association with all three clusters. Mendelian randomization suggested a causal role of BMI and SHBG on PCOS. No causal associations were observed for PCOS on disease outcomes.

Tau aggregation in neurofibrillary tangles (NFTs) is closely associated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, the molecular signatures that distinguish between aggregation-prone and aggregation-resistant cell states are unknown. We developed methods for the high-throughput isolation and transcriptome profiling of single somas with NFTs from the human AD brain, quantified the susceptibility of 20 neocortical subtypes for NFT formation and death, and identified both shared and cell-type-specific signatures. NFT-bearing neurons shared a marked upregulation of synaptic transmission-related genes, including a core set of 63 genes enriched for synaptic vesicle cycling. Oxidative phosphorylation and mitochondrial dysfunction were highly cell-type dependent. Apoptosis was only modestly enriched, and the susceptibilities of NFT-bearing and NFT-free neurons for death were highly similar. Our analysis suggests that NFTs represent cell-type-specific responses to stress and synaptic dysfunction. We provide a resource for biomarker discovery and the investigation of tau-dependent and tau-independent mechanisms of neurodegeneration.