Haijun Qiu

The psychosis spectrum in a young U.S. community sample: findings from the Philadelphia Neurodevelopmental Cohort

Little is known about the occurrence and predictors of the psychosis spectrum in large non‐clinical community samples of U.S. youths. We aimed to bridge this gap through assessment of psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort, a collaborative investigation of clinical and neurobehavioral phenotypes in a prospectively accrued cohort of youths, funded by the National Institute of Mental Health. Youths (age 11‐21; N=7,054) and collateral informants (caregiver/legal guardian) were recruited through the Childrens Hospital of Philadelphia and administered structured screens of psychosis spectrum symptoms, other major psychopathology domains, and substance use. Youths were also administered a computerized neurocognitive battery assessing five neurobehavioral domains. Predictors of psychosis spectrum status in physically healthy participants (N=4,848) were examined using logistic regression. Among medically healthy youths, 3.7% reported threshold psychotic symptoms (delusions and/or hallucinations). An additional 12.3% reported significant sub‐psychotic positive symptoms, with odd/unusual thoughts and auditory perceptions, followed by reality confusion, being the most discriminating and widely endorsed attenuated symptoms. A minority of youths (2.3%) endorsed subclinical negative/disorganized symptoms in the absence of positive symptoms. Caregivers reported lower symptom levels than their children. Male gender, younger age, and non‐European American ethnicity were significant predictors of spectrum status. Youths with spectrum symptoms had reduced accuracy across neurocognitive domains, reduced global functioning, and increased odds of depression, anxiety, behavioral disorders, substance use and suicidal ideation. These findings have public health relevance for prevention and early intervention.

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ2 meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico–replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.

GWAS of blood cell traits identifies novel associated loci and epistatic interactions in Caucasian and African-American children

Hematological traits are important clinical indicators, the genetic determinants of which have not been fully investigated. Common measures of hematological traits include red blood cell (RBC) count, hemoglobin concentration (HGB), hematocrit (HCT), mean corpuscular hemoglobin (MCH), MCH concentration (MCHC), mean corpuscular volume (MCV), platelet count (PLT) and white blood cell (WBC) count. We carried out a genome-wide association study of the eight common hematological traits among 7943 African-American children and 6234 Caucasian children. In African Americans, we report five novel associations of HBE1 variants with HCT and MCHC, the alpha-globin gene cluster variants with RBC and MCHC, and a variant at the ARHGEF3 locus with PLT, as well as replication of four previously reported loci at genome-wide significance. In Caucasians, we report a novel association of variants at the COPZ1 locus with PLT as well as replication of four previously reported loci at genome-wide significance. Extended analysis of an association observed between MCH and the alpha-globin gene cluster variants demonstrated independent effects and epistatic interaction at the locus, impacting the risk of iron deficiency anemia in African Americans with specific genotype states. In summary, we extend the understanding of genetic variants underlying hematological traits based on analyses in African-American children.

The Philadelphia Neurodevelopmental Cohort: A publicly available resource for the study of normal and abnormal brain development in youth.

The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale study of child development that combines neuroimaging, diverse clinical and cognitive phenotypes, and genomics. Data from this rich resource is now publicly available through the Database of Genotypes and Phenotypes (dbGaP). Here we focus on the data from the PNC that is available through dbGaP and describe how users can access this data, which is evolving to be a significant resource for the broader neuroscience community for studies of normal and abnormal neurodevelopment.

Duplication of the SLIT3 Locus on 5q35.1 Predisposes to Major Depressive Disorder

Major depressive disorder (MDD) is a common psychiatric and behavioral disorder. To discover novel variants conferring risk to MDD, we conducted a whole-genome scan of copy number variation (CNV), including 1,693 MDD cases and 4,506 controls genotyped on the Perlegen 600K platform. The most significant locus was observed on 5q35.1, harboring the SLIT3 gene (P = 2×10−3). Extending the controls with 30,000 subjects typed on the Illumina 550 k array, we found the CNV to remain exclusive to MDD cases (P = 3.2×10−9). Duplication was observed in 5 unrelated MDD cases encompassing 646 kb with highly similar breakpoints. SLIT3 is integral to repulsive axon guidance based on binding to Roundabout receptors. Duplication of 5q35.1 is a highly penetrant variation accounting for 0.7% of the subset of 647 cases harboring large CNVs, using a threshold of a minimum of 10 SNPs and 100 kb. This study leverages a large dataset of MDD cases and controls for the analysis of CNVs with matched platform and ethnicity. SLIT3 duplication is a novel association which explains a definitive proportion of the largely unknown etiology of MDD.

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

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.

Electronic Health Record Based Algorithm to Identify Patients with Autism Spectrum Disorder

Objective Cohort selection is challenging for large-scale electronic health record (EHR) analyses, as International Classification of Diseases 9th edition (ICD-9) diagnostic codes are notoriously unreliable disease predictors. Our objective was to develop, evaluate, and validate an automated algorithm for determining an Autism Spectrum Disorder (ASD) patient cohort from EHR. We demonstrate its utility via the largest investigation to date of the co-occurrence patterns of medical comorbidities in ASD. Methods We extracted ICD-9 codes and concepts derived from the clinical notes. A gold standard patient set was labeled by clinicians at Boston Children’s Hospital (BCH) (N = 150) and Cincinnati Children’s Hospital and Medical Center (CCHMC) (N = 152). Two algorithms were created: (1) rule-based implementing the ASD criteria from Diagnostic and Statistical Manual of Mental Diseases 4th edition, (2) predictive classifier. The positive predictive values (PPV) achieved by these algorithms were compared to an ICD-9 code baseline. We clustered the patients based on grouped ICD-9 codes and evaluated subgroups. Results The rule-based algorithm produced the best PPV: (a) BCH: 0.885 vs. 0.273 (baseline); (b) CCHMC: 0.840 vs. 0.645 (baseline); (c) combined: 0.864 vs. 0.460 (baseline). A validation at Children’s Hospital of Philadelphia yielded 0.848 (PPV). Clustering analyses of comorbidities on the three-site large cohort (N = 20,658 ASD patients) identified psychiatric, developmental, and seizure disorder clusters. Conclusions In a large cross-institutional cohort, co-occurrence patterns of comorbidities in ASDs provide further hypothetical evidence for distinct courses in ASD. The proposed automated algorithms for cohort selection open avenues for other large-scale EHR studies and individualized treatment of ASD.

Expanding the SPECC1L mutation phenotypic spectrum to include Teebi hypertelorism syndrome

Teebi hypertelorism syndrome is a rare autosomal dominant disorder that has eluded a molecular etiology since first described in 1987. Here we report on two unrelated families with a Teebi hypertelorism‐like syndrome and Teebi hypertelorism phenotype who have missense mutations in Sperm Antigen With Calponin Homology And Coiled‐Coil Domains (SPECC1L), previously associated with oblique facial clefting and Opitz G/BBB syndrome. The first patient and his affected mother were previously‐reported by Hoffman et al. in this journal as a new syndrome resembling Teebi hypertelorism and Aarskog syndromes in 2007. This patient had hypertelorism, sagittal and coronal craniosynostosis, ptosis, natal teeth, unusual umbilicus, shawl scrotum, small hands, and feet, with grossly normal development. Our second patient had classic Teebi hypertelorism syndrome with hypertelorism and a giant umbilical hernia. Patient one and his affected mother had a c.1260G>C:p.E420D variant and patient two had a de novo c.1198_1203delATACAC:p.I400_H401del variant in SPECC1L. We review the phenotypic findings in the previously‐published Teebi hypertelorism syndrome patients, and the Opitz G/BBB patients with SPECC1L mutations. In addition we emphasize the findings of aortic root dilation and craniosynostosis in these patients, which should be considered in their management.

Common variants in MMP20 at 11q22.2 predispose to 11q deletion and neuroblastoma risk

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.

Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility

BackgroundJuvenile 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.MethodsWe performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed to evaluate the association of the identified rare functional variants.ResultsThe CXCR4 locus on 2q22.1 was found to be significantly associated with JIA, peaking at SNP rs953387. However, this result is subjected to subpopulation stratification within the subjects of European ancestry. After adjusting for principal components, nominal significant association remained (p < 10−4). Because of its interesting known function in immune regulation, we carried out further analyses to assess its relationship with JIA. Expression of CXCR4 was correlated with CXCR4 rs953387 genotypes in lymphoblastoid cell lines (p = 0.014) and T-cells (p = 0.0054). In addition, rare non-synonymous and stop-gain sequence variants in CXCR4, putatively damaging for CXCR4 function, were significantly enriched in JIA cases (p = 0.015).ConclusionOur results suggest the association of CXCR4 variants with JIA, implicating that this gene may be involved in the pathogenesis of autoimmune disease. However, because this locus is subjected to population stratification within the subjects of European ancestry, additional replication is still necessary for this locus to be considered a true risk locus for JIA. This cell-surface chemokine receptor has already been targeted in other diseases and may serve as a tractable therapeutic target for a specific subset of pediatric arthritis patients with additional replication and functional validation of the locus.