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Study Description

This submission includes genotyping data from 6 separate cohorts (named A-E here), each is described in separate paragraphs below.

Cohort A) Autism is a neurodevelopmental disorder that affects 1.5 million people in the United States, at an estimated lifetime cost of $4 million. It is part of Pervasive Developmental Disorder characterized by impairments in communication, language and reciprocal social interaction, and by unusual patterns of restricted and repetitive interests or behaviors. Autism, or autistic disorder, is the most severe form of the disease which has a wide range of symptom severity encompassed by the more inclusive term, Autism Spectrum Disorder (ASD). The prevalence of Autistic Disorder is currently estimated to be 4 per 1000, affecting 4 times more boys than girls. Susceptibility to autism is clearly attributable to genetic factors but the extensive clinical and genetic heterogeneity within the disorder have hindered efforts at genetic dissection. Identifying the genetic variants that contribute to this highly heritable disease is crucial to advancing research on autism. Reported concordance rates among monozygotic twins range from 60% − 90% and heritability of autism has been estimated to be 90% or greater. Identifying genetic variants that contribute to this highly heritable disease is crucial to advancing research on autism.

Cohort B) The long-term objective of this research is to determine the molecular genetic basis of Cardiovascular (CV) disease in the young; this study seeks to identify gene mutations that cause "structural heart defects". Every year in the USA, 32,000 individuals are born with CV malformations; approximately 20% die during the first year of life. Another 30,000 young people develop a disturbance of cardiac rhythm or conduction. In addition, the life expectancy of another 40,000 young people is shortened by other forms of CV disease. It is becoming more apparent that in spite of the success in diagnosis and treatment, very little is known about the causes of CV disease in the young; understanding the causes will permit insight into the pathophysiologic basis of disease and allow definition of disease risk - two critical elements for disease prevention. Disease prevention and/or risk modification promises to be the new frontier in the management of CV disease in the young.

Cohort C) Eosinophilic Esophagitis (EE) is one of the manifestations of eosinophilic gastrointestinal inflammation which have profound effects on a patient's health and development. Results of epidemiologic studies performed through our center demonstrate that eosinophil-associated gastrointestinal disease is not an uncommon entity. While the epidemiology of eosinophilic esophagitis has not been thoroughly studied until recently, there appears to be a significant increase in the diagnosis of EE in the last decade. Based on our research, this mainly reflects increased disease recognition, but there is also a bona-fide increase in disease incidence which coincides with the increasing incidence of asthma and allergic diseases in the industrialized world. In addition, many patients with intractable symptoms thought in the past to represent atypical GERD or other disorders are now being recognized as having EE. Diagnosis of EE requires endoscopy and biopsies to document the characteristic histologic findings of esophageal eosinophilia. In general, this study proposed to elucidate the mechanisms underlying eosinophil growth, survival, migration, and function, and to investigate and further characterize the pathophysiology of, clinical manifestations of, and spectrum of disease severity of eosinophilic esophagitis in humans.

Cohort D) Juvenile idiopathic arthritis (JIA) is a debilitating complex genetic disorder characterized by inflammation of the joints and other tissues and shares histopathological features with other autoimmune diseases. It is considered a complex genetic disorder. There are more than 50,000 children with JIA in the USA, approximately 1 per 1000 births, which is about the same incidence as juvenile diabetes. It is believed that genes in the major histocompatibility complex (MHC) play a role in defining genetic risk, and it can be hypothesized that loci in other chromosomal regions are involved in conferring risk in JIA. These candidate chromosomal regions can be identified using genome wide association analyses. The long-term goal is a comprehensive understanding of the genetic basis of these disabling arthropathies for which the molecular basis is not presently understood. The results of recent GWAS for Caucasian JIA were recently published in Arthritis Rheum. 2012 Feb 21 (Published online, PMID=22354554).

Cohort E) Childhood Absence Epilepsy (CAE) is characterized by very frequent (several to many per day) absence seizures in an otherwise normal child with an EEG usually demonstrating 3 Hz bilateral, synchronous, symmetrical spikewaves pattern with normal background activity. CAE occurs in 10% to 15% of all children with epilepsy with an annual incidence of 6.3 to 8/100,000 in children <15 years of age. Females are more affected than males. Epilepsy onset is typically between the ages of 4 to 8 years with a peak incidence of 6 to 7 years. CAE does not start after age 13 years. The primary objective of this study is: To identify the optimal anticonvulsant (i.e. the antiepileptic drug (AED) with highest rate of seizure control and lowest incidence of treatment limiting toxicity) used for the initial treatment of children with Childhood Absence Epilepsy (CAE). The secondary objectives are: To determine the pharmacogenetic and other non-heritable factors underlying the interindividual variation in anticonvulsant response efficacy and toxicity. To define and contrast the effects of ethosuximide, lamotrigine, and valproic acid monotherapy on cognition (attention), behavior and quality of life in children with Childhood Absence Epilepsy.

Cohort F) Cincinnati Controls. These are local healthy children selected to be representative of the population of Cincinnati with respect to gender and ancestry.

Cohort G) Cytogenetics cases are ascertained by the clinical request to obtain cytogenetic analysis. The platform used included genotyping data which are then available for genome wide association analysis

  • Study Type: Cohort
  • dbGaP estimated ancestry components using GRAF-pop
  • Number of study subjects that have individual level data available through Authorized Access: 4562

Authorized Access
Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

Cohorts A through G. All submitted genotyping records are from patients with electronic medical records at CCHMC.

Cohort A) Autism. The cases for this cohort comprise a subgroup of autism defined by a history of developmental regression. To ensure as homogeneous a sample as possible, subjects were included if they met criteria for Autistic Disorder by clinical evaluation, and confirmed by the Autism Diagnostic Observation Schedule (ADOS). Children were excluded from the study if they had a diagnosis of a developmental disorder in addition to autism, such as Down syndrome, Tuberous Sclerosis or Fragile X syndrome. Children with epilepsy or a history of seizures were not excluded.

Cohort B) Cardiovascular (CV) disease. Based on the initial interview, a determination of the likelihood of familial CV disease in the young was made, and subjects were divided into two groups − two or more family members with CV disease in the young (familial) or no additional family history of CV disease in the young (nonfamilial). Probands were identified through their pediatric cardiologists.

Inclusion − a diagnosis of cardiovascular disease in the young without regard to sex, age, or race in the proband; family members of probands were invited to participate. There is no known ethnic/racial predilection for cardiovascular disease in the young.

Exclusion − known genetic diagnosis (e.g. trisomy 21, chromosome 22q11 deletion, and any other cytogenetic abnormality) or certain phenotypes (e.g. hypertrophic cardiomyopathy, Marfan's syndrome, etc.).

Cohort C) Eosinophilic Esophagitis (EE). Individuals were required to meet at least one criterion from the list below in order to be included in the original study. Background information was required to analyze the data thoroughly including medical history, slides, and pathology reports, as well as information from CCHMC medical records:

  1. Patients undergoing diagnostic endoscopy, colonoscopy, venipuncture, and/or atopy testing at Cincinnati Children's Hospital Medical Center.
  2. Patients cared for in CCHMC clinics, for example, Allergy/Immunology and Gastroenterology.
  3. Participants could be no younger than one year of age and no older than 65 years of age.
  4. Family members of patients diagnosed with an eosinophilic disorder.
  5. Healthy human volunteers, including employees recruited from the laboratories at the Cincinnati Children's Research Foundation and the Cincinnati Genomic Control Cohort.

Cohort D) Juvenile idiopathic arthritis (JIA). Inclusion: Patients were required to have an established or probable diagnosis of oligoarthritis, extended oligoarthritis or polyarthritis (RF positive or negative) or systemic JIA as determined by International League Against Rheumatism criteria. (Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, He X, Maldonado-Cocco J, Orozco-Alcala J, Prieur AM, Suarez-Almazor ME, Woo P. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31(2):390-2) PMID: 14760812

Exclusion: The patient was excluded if they had any uncontrolled, clinically significant pre-existing systemic disease unrelated to the primary rheumatic disease, including hepatic, renal, neurological, endocrine, cardiac, gastrointestinal or hematologic conditions. The patient was also excluded if he or she has a history or current substance abuse or psychiatric problem that, in the investigator's opinion, would interfere with the ability to give informed consent or comply with study requirements or physician instructions.

Cohort E) Childhood Absence Epilepsy (CAE). The original study was a parallel, randomized, double blinded study, with partial crossover to open label at treatment failure only. Three AEDs, ethosuximide (ETX), lamotrigine (LTG), and valproic acid (VPA) were compared as initial monotherapy in children with Childhood Absence Epilepsy (CAE) who weighed at least 10 kg and were older than 2.5 years old and younger than 13 years old at study entry.

  1. Diagnosis: Clinical diagnosis of Childhood Absence Epilepsy consistent with the International League against Epilepsy Proposal for Revised Classification of Epilepsies and Epileptic Syndromes.
  2. EEG: Interictal EEG demonstrating bilateral synchronous symmetrical approximate 3 Hz spike waves on a normal background with at least one burst lasting ≥3 seconds.
  3. Age > 2.5 years and < 13 years of age at study entry.
  4. Body weight ≥ 10 kilograms.
  5. Body Mass Index: BMI for age < 99th percentile.
  6. Hepatic AST/ALT < 2.5 times the upper limit of normal and Total bilirubin < 1.5 times the upper limit of normal.
  7. Hematologic: Absolute neutrophil count ≥1500/mm3, platelets ≥ 120, 000 /mm3.
  8. Female subjects had to be premenarchal at the time of enrollment and willing to agree to abstinence for the duration of the study.
  9. Parent/legal guardian(s) willing to sign an IRB approved informed consent.
  10. Subject assent (when appropriate and as dictated by local IRB).

Exclusion Criteria

  1. Treatment for CAE with AEDs for a period of greater than 14 days prior to randomization.
  2. History of a major psychiatric disease (e.g. psychosis, major depression).
  3. History of autism or pervasive development disorder.
  4. History of non-febrile seizures other than typical absence seizures. This includes a history of an afebrile generalized tonic clonic seizure.
  5. Clinical signs and symptoms consistent with a diagnosis of juvenile absence epilepsy or juvenile myoclonic epilepsy as delineated by the International League against Epilepsy Proposal for Revised Classification of Epilepsies and Epileptic Syndromes.
  6. History of recent or present significant medical disease (i.e, cardiovascular, hepatic, renal, gynecologic, musculoskeletal, metabolic or endocrine).
  7. History of a severe dermatologic reaction (e.g. Stevens Johnson, toxic Epidermolysis Necrosis) to medication.
  8. Subject or parent/legal guardian might not be reasonably expected to be compliant with or to complete the study.
  9. Participation in a trial of an investigational drug or device within 30 days prior to screening.
  10. Use of systemic contraceptive for any indication, including acne.

Cohort F) Cincinnati Controls. There are no inclusion or exclusion criteria, except that the subject must have been a resident of Cincinnati at the time of enrollment. These children were ascertained to reflect the local population.

Cohort G) Cytogenetics. There are no inclusion or exclusion criteria except that they be ascertained through their being evaluated by cytogenetics testing at CCHMC.

Study History

Cohort A) Autism. These are local CCHMC cases that were contributed to a larger study. They have previously been evaluated to report significant evidence for linkage on 21q and 7q in a subset of relative pairs affected by autism (Molloy et al. Mol Psychiatry. 2005 Aug;10(8):741-6; PMID: 15940295).

Cohort B) Cardiovascular (CV) disease. CV disease in the young is genetically heterogeneous. For example, tetralogy of Fallot has been associated with deletion of chromosome 22q11, trisomy 21 and mutations in TBX5, Jagged1 and Nkx2.5. Recognition of the genetic basis of CV disease in the young can be improved by using genetic models incorporating variable expressivity (individuals with the same gene mutation have different phenotypes) and reduced penetrance (some genotype positive individuals appear to have no phenotype). Other active projects include positional cloning and candidate gene analysis in 5p15-linked familial Atrial Septal Defect (ASD), and use of linkage analysis, positional cloning and candidate gene evaluation to study congenital heart defects, cardiomyopathies and disturbances of cardiac rhythm and conduction (long QT syndrome, Wolff-Parkinson-White syndrome and atrioventricular block). Additionally, there is ongoing characterization of genotype-phenotype relations of known genes whose mutations cause CV disease in the young (e.g. NKX2.5 and TBX5). These are cases of CV disease evaluated at CCHMC.

Cohort C) Eosinophilic Esophagitis (EE). Although the etiology of EE is unknown, several lines of evidence support an allergic cause, including the high incidence of atopy in patients with EE, the improvement in patient symptoms on an allergen-free diet, and the common findings of mast cell degranulation and mediators in tissue and stool samples. Prior work done in this area has focused on learning more about the biology of the eosinophil in vitro. One molecule that appears to be important in regulating eosinophilia is IL-5. This cytokine regulates the selective growth and differentiation of eosinophil progenitor cells and the post-mitotic survival and activation of mature eosinophils. Another molecule is eotaxin and its related family members eotaxin-2 and eotaxin-3, a set of eosinophil-specific chemokines. Previously, we have shown that EE appears to have a strong genetic component based on the frequent presence of a familial inheritance pattern and the high sibling risk ratio (#&126;80-fold). Based on screening a custom DNA array containing 738 SNPs, we have identified an association of EE with SNPs associated with the gene encoding thymic stromal lymphopoietin (TSLP), a key cytokine known to regulate Th2 cell polarization. Notably, using an independent genome wide association study (GWAS) approach, we have preliminarily linked EE with the same promising genetic locus (chromosome 5q22 near the TSLP and WDR36 genes). Our central hypothesis is that EE has strong genetic components that can be elucidated by a candidate gene approach focused on genes involved in asthma and allergy and by a GWAS analysis. These are cases of EE evaluated clinically at CCHMC.

Cohort D) Juvenile idiopathic arthritis (JIA). Prior studies have focused on both genes and gene expression in JIA with both subtype specific differences being demonstrated. The genome effect initially focused on the MHC (or HLA region). Several associations have been described and the field reviewed. Age sensitivity of these genetic effects is substantial. With the accumulation of multiplex as well as simplex JIA families we were able to study linkage between JIA and HLA and this has been demonstrated for both pauciarticular and polyarticular onset disease. While non-MHC genes to date have proven harder to find than HLA region genes, several candidate genes have been identified including a T-cell receptor null gene (Vß6.1) and, more recently, cytokine gene effects for IL6 and IL4 have been documented. All of the cases submitted were evaluated at CCHMC.

Cohort E) Childhood Absence Epilepsy (CAE). Childhood Absence Epilepsy (CAE) is the most common childhood epilepsy syndrome. Although our recent clinical trial of 446 children with CAE found ethosuximide as optimal initial short term therapy, is it not clear how short term results relate to long term outcomes. Optimal long term therapy can be determined by following these children for four more years. In its first 6 years, the 32 center CAE trial successfully completed a double blind randomized controlled comparative trial comparing short term outcomes for ethosuximide, lamotrigine and valproic acid as initial therapy for children with newly diagnosed CAE characterized by only absence seizures. The CAE trial established ethosuximide as the optimal initial short term therapy for children with newly diagnosed CAE. All of the cases submitted were evaluated at CCHMC.

Cohort F) Cincinnati Controls. This was designed to be a sample of controls to use in genetic and other studies at CCHMC. All of the controls submitted have an electronic medical record at CCHMC.

Cohort G) Cytogenetics. Since 2008, the Cytogenetics Laboratory at CCHMC has used Illumina genotyping arrays containing 660,000 or 1.2 million markers for cytogenetic analysis. This cohort contains the genotyping data records and demographics from patients in which this analysis was performed as a component of their clinical care.

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