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.

Absence of the anterior (ACL) or posterior cruciate ligament (PCL) are rare congenital malformations that result in knee joint instability, with a prevalence of 1.7 per 100,000 live births and can be associated with other lower-limb abnormalities such as ACL agnesia and absence of the menisci of the knee. While a few cases of absence of ACL/PCL are reported in the literature, a number of large familial case series of related conditions such as ACL agnesia suggest a potential underlying monogenic etiology. We performed whole exome sequencing of a family with two individuals affected by ACL/PCL.

In addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation.

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.

Heart failure is a complex clinical syndrome and has become the most common reason for adult hospitalization in developed countries. Two subtypes of heart failure, ischemic heart disease (ISCH) and dilated cardiomyopathy (DCM), have been studied using microarray platforms. However, microarray has limited resolution. Here we applied RNA sequencing (RNA-Seq) to identify gene signatures for heart failure from six individuals, including three controls, one ISCH and two DCM patients. Using genes identified from this small RNA-Seq dataset, we were able to accurately classify heart failure status in a much larger set of 313 individuals. The identified genes significantly overlapped with genes identified via genome-wide association studies for cardiometabolic traits and the promoters of those genes were enriched for binding sites for transcriptions factors. Our results indicate that it is possible to use RNA-Seq to classify disease status for complex diseases such as heart failure using an extremely small training dataset.

In this paper, we present the first evidence that perceived speech can be identified from the listeners' brain signals measured via functional-near infrared spectroscopy (fNIRS)-a non-invasive, portable, and wearable neuroimaging technique suitable for ecologically valid settings. In this study, participants listened audio clips containing English stories while prefrontal and parietal cortices were monitored with fNIRS. Machine learning was applied to train predictive models using fNIRS data from a subject pool to predict which part of a story was listened by a new subject not in the pool based on the brain's hemodynamic response as measured by fNIRS. fNIRS signals can vary considerably from subject to subject due to the different head size, head shape, and spatial locations of brain functional regions. To overcome this difficulty, a generalized canonical correlation analysis (GCCA) was adopted to extract latent variables that are shared among the listeners before applying principal component analysis (PCA) for dimension reduction and applying logistic regression for classification. A 74.7% average accuracy has been achieved for differentiating between two 50 s. long story segments and a 43.6% average accuracy has been achieved for differentiating four 25 s. long story segments. These results suggest the potential of an fNIRS based-approach for building a speech decoding brain-computer-interface for developing a new type of neural prosthetic system.

To date, most transcriptome studies of schizophrenia focus on the analysis of protein-coding genes. Long noncoding RNAs (lncRNAs) are emerging as key tissue-specific regulators of cellular and disease processes. The amygdala brain region has been implicated in the pathophysiology of schizophrenia. We performed unbiased whole transcriptome profiling of amygdala tissues from 22 schizophrenia patients and 24 non-psychiatric controls using RNA-seq. We reconstructed amygdala transcriptome and employed systems biology approaches to annotating the functional roles of lncRNAs. As a result, we identified 839 novel lncRNAs in amygdala. We found in amygdala lncRNAs are more subtype-specific than protein-coding genes. We identified functional modules associated with "synaptic transmission", "ribosome", and "immune responses" which were related to schizophrenia pathophysiology that involved lncRNAs. Integrative functional analyses associating individual lncRNAs with specific pathways and functions further show that amygdala lncRNAs are connected with all of these pathways. Our study presents the first systematic landscape of lncRNAs in amygdala tissue from schizophrenia cases.

Inherited syndromic retinopathies are a highly heterogeneous group of diseases that involve retinal anomalies and systemic manifestations. They include retinal ciliopathies, other well-defined clinical syndromes presenting with retinal alterations and cases of non-specific multisystemic diseases. The heterogeneity of these conditions makes molecular and clinical characterization of patients challenging in daily clinical practice. We explored the capacity of targeted resequencing and copy-number variation analysis to improve diagnosis of a heterogeneous cohort of 47 patients mainly comprising atypical cases that did not clearly fit a specific clinical diagnosis. Thirty-three likely pathogenic variants were identified in 18 genes (ABCC6, ALMS1, BBS1, BBS2, BBS12, CEP41, CEP290, IFT172, IFT27, MKKS, MYO7A, OTX2, PDZD7, PEX1, RPGRIP1, USH2A, VPS13B, and WDPCP). Molecular findings and additional clinical reassessments made it possible to accurately characterize 14 probands (30% of the total). Notably, clinical refinement of complex phenotypes was achieved in 4 cases, including 2 de novo OTX2-related syndromes, a novel phenotypic association for the ciliary CEP41 gene, and the co-existence of biallelic USH2A variants and a Koolen-de-Vries syndrome-related 17q21.31 microdeletion. We demonstrate that combining next-generation sequencing and CNV analysis is a comprehensive and useful approach to unravel the extensive phenotypic and genotypic complexity of inherited syndromic retinopathies.

This study aimed to identify the genetics underlying dominant forms of inherited retinal dystrophies using whole exome sequencing (WES) in six families extensively screened for known mutations or genes. Thirty-eight individuals were subjected to WES. Causative variants were searched among single nucleotide variants (SNVs) and insertion/deletion variants (indels) and whenever no potential candidate emerged, copy number variant (CNV) analysis was performed. Variants or regions harboring a candidate variant were prioritized and segregation of the variant with the disease was further assessed using Sanger sequencing in case of SNVs and indels, and quantitative PCR (qPCR) for CNVs. SNV and indel analysis led to the identification of a previously reported mutation in PRPH2. Two additional mutations linked to different forms of retinal dystrophies were identified in two families: a known frameshift deletion in RPGR, a gene responsible for X-linked retinitis pigmentosa and p.Ser163Arg in C1QTNF5 associated with Late-Onset Retinal Degeneration. A novel heterozygous deletion spanning the entire region of PRPF31 was also identified in the affected members of a fourth family, which was confirmed with qPCR. This study allowed the identification of the genetic cause of the retinal dystrophy and the establishment of a correct diagnosis in four families, including a large heterozygous deletion in PRPF31, typically considered one of the pitfalls of this method. Since all findings in this study are restricted to known genes, we propose that targeted sequencing using gene-panel is an optimal first approach for the genetic screening and that once known genetic causes are ruled out, WES might be used to uncover new genes involved in inherited retinal dystrophies.

Although mitochondrial dysfunction has been implicated in the pathophysiology of attention deficit and hyperactivity disorder ADHD, the role of mitochondrial DNA (mtDNA) has not been extensively investigated. To determine whether mtDNA haplogroups influence risk of ADHD, we performed a case-control study comprising 2076 ADHD cases and 5078 healthy controls, all of whom were European decedents recruited from The Children's Hospital of Philadelphia (CHOP). Associations between eight major European mtDNA Haplogroups and ADHD risk were assessed in three independent European cohorts. Meta-analysis of the three studies indicated that mtDNA haplogroups K (odds ratio = 0.69, P = 2.24 × 10-4, Pcorrected = 1.79 × 10-3) and U (odds ratio = 0.77, P = 8.88 × 10-4, Pcorrected = 7.11 × 10-3) were significantly associated with reduced risk of ADHD. In contrast, haplogroup HHV* (odds ratio = 1.18, P = 2.32 × 10-3, Pcorrected = 0.019) was significantly associated with increased risk of ADHD. Our results provide novel insight into the genetic basis of ADHD, implicating mitochondrial mechanisms in the pathophysiology of this relatively common psychiatric disorder.

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.

Citrus huanglongbing (HLB) is a severe problem for citrus cultivation. The disease management programs benefit from improved field tools suitable for surveying the ACP vector (Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Psyllidae)) and the associated pathogen. In the present study, we utilize three-dimensional (3D) printers and design tools to develop traps that can capture and preserve ACPs. Three novel, 3D-printed traps were designed and evaluated: stem trap, and cylinder traps 1 and 2. The traps and yellow sticky cards were deployed weekly for 8 months in 2 non-commercial citrus groves in Florida; in California, the traps were evaluated for 12 months in field cages and 4 citrus groves. The stem traps captured lower numbers of ACPs at all experimental sites compared to the cylinder traps. Capture rates in the cylinder traps were comparable to the sticky trap, making the device a viable tool for monitoring field ACPs. The two main advantages of using the reusable 3D traps over standard methods of ACP and HLB surveys include dynamic sampling that can be conducted year-round and the capture of ACPs that can be preserved and tested. Improved trapping may facilitate quick management decisions and mitigate HLB.

Dromaeosaurids were bird-like dinosaurs with a predatory ecology known to forage on fish, mammals and other dinosaurs. We describe Daurlong wangi gen. et sp. nov., a dromaeosaurid from the Lower Cretaceous Jehol Biota of Inner Mongolia, China. Exceptional preservation in this specimen includes a large bluish layer in the abdomen which represents one of the few occurrences of intestinal remnants among non-avian dinosaurs. Phylogenetically, Daurlong nests among a lineage of short-armed Jehol Biota species closer to eudromaeosaurs than microraptorines. The topographic correspondence between the exceptionally preserved intestine in the more stem-ward Scipionyx and the remnants in the more birdlike Daurlong provides a phylogenetic framework for inferring intestine tract extent in other theropods lacking fossilized visceral tissues. Gastrointestinal organization results conservative among faunivorous dinosaurs, with the evolution of a bird-like alimentary canal restricted to avialan theropods.

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.

Phosphorylation events direct the flow of signals and metabolites along cellular protein networks. Current annotations of kinase-substrate binding events are far from complete. In this study, we scanned the entire human protein sequences using the PROSITE domain annotation tool to identify patterns of domain composition in kinases and their substrates. We identified statistically enriched pairs of strings of domains (signature pairs) in kinase-substrate couples presented in the 2006 version of the PTM database.

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.

Understanding the influence of gene expression on the molecular mechanisms underpinning human phenotypic diversity is fundamental to being able to predict health outcomes and treat disease. We have carried out whole transcriptome expression analysis on a series of eight normal human postmortem eyes by RNA sequencing. Here we present data showing that ∼80% of the transcriptome is expressed in the posterior layers of the eye and that there is significant differential expression not only between the layers of the posterior part of the eye but also between locations of a tissue layer. These differences in expression also extend to alternative splicing and splicing factors. Differentially expressed genes are enriched for genes associated with psychiatric, immune and cardiovascular disorders. Enrichment categories for gene ontology included ion transport, synaptic transmission and visual and sensory perception. Lastly, allele-specific expression was found to be significant for CFH, C3 and CFB, which are known risk genes for age-related macular degeneration. These expression differences should be useful in determining the underlying biology of associations with common diseases of the human retina, retinal pigment epithelium and choroid and in guiding the analysis of the genomic regions involved in the control of normal gene expression.

Hundreds of genomic loci have been identified with the recent advances of schizophrenia in genome-wide association studies (GWAS) and sequencing studies. However, the functional interactions among those genes remain largely unknown. We developed a network-based approach to integrate multiple genetic risk factors, which lead to the discovery of new susceptibility genes and causal sub-networks, or pathways in schizophrenia. We identified significantly and consistently over-represented pathways in the largest schizophrenia GWA studies, which are highly relevant to synaptic plasticity, neural development and signaling transduction, such as long-term potentiation, neurotrophin signaling pathway, and the ERBB signaling pathway. We also demonstrated that genes targeted by common SNPs are more likely to interact with genes harboring de novo mutations (DNMs) in the protein-protein interaction (PPI) network, suggesting a mutual interplay of both common and rare variants in schizophrenia. We further developed an edge-based search algorithm to identify the top-ranked gene modules associated with schizophrenia risk. Our results suggest that the N-methyl-D-aspartate receptor (NMDAR) interactome may play a leading role in the pathology of schizophrenia, as it is highly targeted by multiple types of genetic risk factors.

Rubinstein-Taybi syndrome (RTS) is a rare, congenital, plurimalformative, and neurodevelopmental disorder. Previous studies have reported that large deletions contribute to more severe RTS phenotypes than those caused by CREBBP point mutations, suggesting a concurrent pathogenetic role of flanking genes, typical of contiguous gene syndromes, but the detailed genetics are unclear.

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.