Genomic basis of pediatric bipolar disorder

小儿双相情感障碍的基因组基础

• 批准号: 9756461
• 负责人: Ikeoluwa Motunrayo Adeshina
• 金额: $ 4.25万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-06 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756461
• 关键词: Adolescent; Adoption; Adult; Affect; Age; Algorithms; Bipolar Disorder; Blood specimen; Candidate Disease Gene; Child; Childhood; Chromosome abnormality; Clinical; Comorbidity; Complement; Complex; Consent; Copy Number Polymorphism; Custom; DNA; DNA sequencing; Data; Diagnosis; Dideoxy Chain Termination DNA Sequencing; Disease; Environmental Risk Factor; Etiology; Family; Family Study; Family member; Frequencies; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genome; Genomics; Genotype; Heritability; Individual; Inherited; Institutes; Institution; Laboratories; Large-Scale Sequencing; Lead; Manic; Measures; Medical; Mental Depression; Mental Health; Mental disorders; Mission; Mosaicism; National Institute of Mental Health; Nucleotides; Parents; Participant; Pathway Analysis; Patients; Periodicity; Personal Communication; Phenotype; Population; Prevalence; Psychotic Disorders; Pythons; Recurrence; Research; Risk; Sampling; Sampling Studies; Sensitivity and Specificity; Siblings; Single Nucleotide Polymorphism; Structure; Techniques; Technology; Training; Twin Multiple Birth; Variant; Visit; base; bipolar spectrum; burden of illness; childhood bipolar disorder; cohort; design; disease mechanisms study; disturbance in affect; early onset disorder; exome sequencing; experience; genetic architecture; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic tools; hypomania; innovation; insertion/deletion mutation; neuropsychiatric disorder; novel; outcome forecast; proband; rare variant; repository; reproductive fitness; study population; therapeutic target; tool; trait; whole genome

PROJECT SUMMARY/ABSTRACT Bipolar spectrum disorder (BPD) is a severe neuropsychiatric disorder of mood disturbance. Individuals with BPD experience cyclical periods of mania or hypomania and depression, and in some cases, psychosis. With a lifetime prevalence of 3.9% in the U.S. adult population, BPD has been regarded as a common disease with a complex etiology. Various studies have categorized BPD based on age at onset. Pediatric BPD has become an established diagnosis and may be regarded as a subclass of BPD. These children have phenotypically more severe conditions than the average adult BPD patient. Although it is known that major gene effects are more likely in early-onset disorders, this subclass of BPD has remained largely uncharacterized from a genomics perspective. We employ the use of an extreme trait design in which whole genome sequencing analysis of a modest sized, carefully selected sample of a bipolar disorder population with extreme phenotypes will likely identify rare variants with modest to high effect sizes enriched for in this population. First, we determine the phenotype and genotype of our pediatric BPD cohort (Specific Aim 1). Trained experts will diagnose and clinically characterize probands (n=100), including their comorbidities, and meticulously document the phenotypes of their parents (n=175) and siblings (n=40). Blood samples will be collected from all participants. Whole genome sequencing (WGS) of probands will be performed using 10X Genomics technology, a recently introduced extension of WGS, with parents and siblings sequenced using standard short-read technology. Our laboratory will then use state-of-the-art genomic analysis tools and techniques to elucidate the genomic landscape of pediatric BPD by identifying highly penetrant and deleterious de novo, mosaic and inherited rare variants conferring risk (Specific Aim 2). Variant annotation and prioritization will be performed to determine candidate variants and Sanger sequencing will be used to validate these. Functional enrichment and pathway analyses will be used to functionally characterize candidate genes. To achieve robust and unbiased results, we propose to further validate our findings and measure recurrence rates in a replication cohort of children diagnosed with bipolar disorder. In order to determine the significance of our genomic findings in pediatric BPD to the occurrence of bipolar disorder in the adult population, we will assess their frequency within recent large-scale genomic sequencing studies of BPD (Specific Aim 3). We expect to find more rare, penetrant, deleterious genomic variants of significance to the study population, with possibly broader implications in the adult BPD population. This study employs novel and innovative approaches by the specific focus on a pediatric bipolar disorder population with severe phenotypic presentations and the use of advanced genomic tools and technologies. In conducting this research, we will contribute to the understanding of the genetic bases of a burdensome mental health condition of relevance to the mission of the National Institute of Mental Health.

项目总结/文摘