Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA.

Calcium, magnesium, potassium, sodium, chloride and phosphorus are the major dietary minerals involved in various biological functions and are commonly measured in the blood serum. Sufficient mineral intake is especially important for children due to their rapid growth. Currently, the genetic mechanisms influencing serum mineral levels are poorly understood, especially for children. We carried out a genome-wide association (GWA) study on 5,602 European-American children and 4,706 African-American children who had mineral measures available in their electronic medical records (EMR). While no locus met the criteria for genome-wide significant association, our results demonstrated a nominal association of total serum calcium levels with a missense variant in the calcium -sensing receptor (CASR) gene on 3q13 (rs1801725, P = 1.96 × 10(-3)) in the African-American pediatric cohort, a locus previously reported in Caucasians. We also confirmed the association result in our pediatric European-American cohort (P = 1.38 × 10(-4)). We further replicated two other loci associated with serum calcium levels in the European-American cohort (rs780094, GCKR, P = 4.26 × 10(-3); rs10491003, GATA3, P = 0.02). In addition, we replicated a previously reported locus on 1q21, demonstrating association of serum magnesium levels with MUC1 (rs4072037, P = 2.04 × 10(-6)). Moreover, in an extended gene-based association analysis we uncovered evidence for association of calcium levels with the previously reported gene locus DGKD in both European-American children and African-American children. Taken together, our results support a role for CASR and DGKD mediated calcium regulation in both African-American and European-American children, and corroborate the association of calcium levels with GCKR and GATA3, and the association of magnesium levels with MUC1 in the European-American children.

Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes.

Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ∼2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P = 5.66×10⁻¹¹) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P = 3.50×10⁻⁹ resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P = 8.06×10⁻⁹ lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D.

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P ≤ 2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P ≤ 3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P ≤ 4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

MYCN amplification and 11q deletion are two inversely correlated prognostic factors of poor outcome in neuroblastoma. Here we identify common variants at 11q22.2 within MMP20 that associate with neuroblastoma cases harboring 11q deletion (rs10895322), using GWAS in 113 European-American cases and 5109 ancestry-matched controls. The association is replicated in 44 independent cases and 1902 controls. Our study yields novel insights into the genetic underpinnings of neuroblastoma, demonstrating that the inherited common variants reported contribute to the origin of intra-tumor genetic heterogeneity in neuroblastoma.Chromosomal abnormalities such as 11q deletion are associated with poor prognosis in neuroblastoma. Here, the authors perform a genome-wide association study and identify an association between a variant within a Matrix metalloproteinase (MMP) gene member, MMP20, and 11q-deletion subtype neuroblastoma.

Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.

We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10-7; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.

In adult mammals, axon regeneration is limited within the lesion site after injury to the optic nerve. Changes in the microenvironment of lesion sites play an important role in retinal ganglion cells (RGCs) axon regeneration along with other intrinsic factors. In this study, the effect of the lesion site on the microenvironment and axon growth was evaluated using a refined optic nerve crush (ONC) injury model, in which the injury range was extended compared to classical injury. The number of regenerated axons labeled anterogradely with cholera toxin B fragment (CTB) was significantly increased in the long-range crush injury (LI) group compared to the ONC group at distances of 500, 1000 and 1500 µm from the initial site of the injury. These data confirmed that RGC axons can regenerate inside the lesion site. Immunofluorescence and proteomic analysis showed that the microenvironment at the lesion site was highly heterogeneous. The levels of myelin-associated inhibitors, chondroitin-sulfate proteoglycans (CSPGs) and other axon growth inhibitors decreased inside the lesion site compared to the posterior segment of the optic nerve lesion site. The expression of multiple lysosome-related enzymes, metabolic inhibitors including cholesterol esterase, cathepsin B, D, Z and arylsulfatase B (ARSB) were significantly increased inside the lesion site for the LI group compared to the normal optic nerves. Our results suggest that the model of long range optic nerve injury is more useful towards understanding the lesion microenvironment and the endogenous regeneration of RGCs. Also, we showed that myelin and neurocan (a CSPG) are differently expressed in the optic nerve between the interior and posterior lesion sites and may explain why axons cannot reach the brain through the lesion site.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with poorly understood molecular mechanisms that results in significant impairment in children. In this study, we sought to assess the role of rare recurrent variants in non-European populations and outside of coding regions. We generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The cases included 116 African Americans (AA) and 89 European Americans (EA), and the controls included 408 AA and 262 EA. Multiple novel rare recurrent variants were identified in exonic regions, functionally classified as stop-gains and frameshifts for known ADHD genes. Deletion in introns of the protocadherins families and the ncRNA HGB8P were identified in two independent EA ADHD patients. A meta-analysis of the two ethnicities for differential ADHD recurrent variants compared to controls shows a small number of overlaps. These results suggest that rare recurrent variants in noncoding regions may be involved in the pathogenesis of ADHD in children of both AA and EA ancestry; thus, WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD.

Previous studies of attention-deficit hyperactivity disorder (ADHD) have suggested that structural variants (SVs) play an important role but these were mainly studied in subjects of European ancestry and focused on coding regions. In this study, we sought to address the role of SVs in non-European populations and outside of coding regions. To that end, we generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The ADHD cases included 116 African Americans (AA) and 89 of European Ancestry (EA) with SVs in comparison with 408 AA and 262 controls, respectively. Multiple SVs and target genes that associated with ADHD from previous studies were identified or replicated, and novel recurrent ADHD-associated SV loci were discovered. We identified clustering of non-coding SVs around neuroactive ligand-receptor interaction pathways, which are involved in neuronal brain function, and highly relevant to ADHD pathogenesis and regulation of gene expression related to specific ADHD phenotypes. There was little overlap (around 6%) in the genes impacted by SVs between AA and EA. These results suggest that SVs within non-coding regions may play an important role in ADHD development and that WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD.

The rare earth elements and yttrium (REY) in bioapatite from deep-sea sediments are potential proxies for reconstructing paleoenvironmental conditions. However, the REY enrichment mechanism and the reliability of this tracer remain elusive because of the lack of key information from ambient pore water. Here, we report high-resolution geochemical data for pore water, bottom water, and bioapatite from deep-sea sites in the western Pacific. Our results reveal that the benthic flux of REY from the deep sea is less substantial than from the shallow marine realm, resulting in REY-rich sediment. The depth distribution of REY in pore water is opposite to that of bioapatite, and REY patterns and neodymium isotopic compositions are not uniformly distributed within bioapatite. These results indicate alteration of REY and neodymium isotopic compositions during early diagenesis. Therefore, we infer that REY from bioapatite are not robust recorders of the deep marine environment through Earth's history.

Magnesium ions are essential to the basic metabolic processes in the human body. Previous genetic studies indicate that serum magnesium levels are highly heritable, and a few genetic loci have been reported involving regulation of serum magnesium in adults. In this study, we examined if additional loci influence serum magnesium levels in children. We performed a genome-wide association study (GWAS) on 2,267 European-American children genotyped on the Illumina HumanHap550 or Quad610 arrays, sharing over 500,000 markers, as the discovery cohort and 257 European-American children genotyped on the Illumina Human OmniExpress arrays as the replication cohort. After genotype imputation, the strongest associations uncovered were with imputed SNPs residing within the FGFR2 (rs1219515, P = 1.1 × 10(-5)) and PAPSS2 (rs1969821, P = 7.2 × 10(-6)) loci in the discovery cohort, both of which were robustly replicated in our independent patient cohort (rs1219515, P = 3.5 × 10(-3); rs1969821, P = 1.2 × 10(-2)). The associations at the FGFR2 locus were also weakly replicated in a dataset from a previous GWAS of serum magnesium in European adults. Our results indicate that FGFR2 and PAPSS2 may play an important role in the regulation of magnesium homeostasis in children of European-American ancestry.

No abstract available

Traumatic optic neuropathy (TON) describes an injury to the optic nerve following either blunt or penetrating trauma, and remains an important cause of vision loss. No generalized treatment of TON has been established so far to restore the injured optic nerve. We developed an adherent drug-encapsulated bi-layered depot (DBP) as a dual drug vehicle for local treatment to protect the residual retinal ganglion cells (RGCs) and regenerate axons following optic nerve damage. The inner layer of the depot was prepared by co-electrospinning poly(d,l-lactide-co-glycolide acid) (PLGA: 75 : 25) and collagen (COL) with the hydrophobic corticosteroid triamcinolone acetonide (TA) loaded. The outer layer was made of PLGA and the hydrophilic neuroprotective agent Fasudil (FA). The DBP showed suitable morphology, hydrophilicity and mechanical properties, and slowly released TA and FA in vitro by undergoing time-dependent degradation and swelling. All depots showed good biocompatibility with L929 mouse fibroblasts, and DBP was helpful in maintaining the morphology of RGCs in vitro. In addition, direct implantation of DBP at the injured optic nerve in a rat model mitigated inflammation and the death of RGCs, and increased the expression of nerve growth-related protein GAP-43. Therefore, DBP maybe a promising local therapy against TON in future.