Genomic analysis of bipolar disorder in a genetic isolate

遗传分离株中双相情感障碍的基因组分析

• 批准号: 8334562
• 负责人: MAJA BUCAN
• 金额: $ 88.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334562
• 关键词: Address; Affect; Alleles; Amish; Architecture; Autistic Disorder; Bipolar Disorder; Cataloging; Catalogs; Child; Chromatin; Chronic; Code; Collection; Complement; Complex; Data; Data Set; Disease; Disease susceptibility; Etiology; Event; Family; Family member; Frequencies; Functional RNA; Future; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; Goals; Haplotypes; Heritability; Homozygote; Human Genome; Incidence; Individual; Inheritance Patterns; Life; Light; Manic; Maps; Mental Depression; Mental disorders; Molecular; Moods; Mutation; Nuclear Family; Parents; Pathway interactions; Patients; Phenotype; Play; Population; Population Analysis; Positioning Attribute; Predisposition; Prevalence; Reading; Recurrence; Regulatory Element; Research Design; Resources; Risk; Role; Schizophrenia; Sequence Analysis; Single Nucleotide Polymorphism; Suicide; Susceptibility Gene; Testing; Variant; base; comparative; computerized tools; density; family influence; genetic linkage analysis; genetic pedigree; genetic variant; genome sequencing; genome wide association study; hypomania; interest; member; next generation; novel; novel strategies; segregation; therapy development; transmission process; young adult

DESCRIPTION (provided by applicant): Bipolar affective disorder is a life-long, often recurring, chronic mental illness which typically appears in young adulthood and is characterized by fluctuations in mood, including recurrent episodes of mania or hypomania and depression. Lifetime prevalence estimates for bipolar disorders are 1 - 3.7%, and tragically, approximately 10-15% of affected individuals die of suicide. A long term goal of our studies is to identify the molecular events that underlie bipolar disorder. To complement ongoing large-scale genome-wide association studies, we focus on an exceptionally large Amish family with high incidence/prevalence and risk of developing bipolar disorder to identify common and rare variants, single nucleotide polymorphisms and structural variants associated with disease susceptibility. We propose to combine high-density SNP genotyping (on all individuals) with next- generation sequencing (on a selected subset) to extract maximum value from the complete understanding of genetic variation in this genetic isolate. To achieve this goal, we propose a three- step strategy: a) to establish a high-density genotype map for all 450 well-phenotyped family members in the pedigree segregating bipolar disorder using Illumina Omni2.5-Quad arrays; b) to generate, in an unbiased way, a full spectrum of genetic variants by whole genome sequencing of 60 individuals (20 parent-child trios), from genomically defined subfamilies and with different disease status (affected and unaffected); and c) to infer a spectrum of identified mutations (rare single nucleotide polymorphisms and structural variants) to the entire pedigree, specifically to unsequenced family members that harbor overlapping haplotypes, (Li et al., 2009; Howie et al., 2010). This variant imputation will use correlation between SNP markers on the genotype platform available for all 450 subjects and SNPs identified by deep sequencing, to predict positions and genotypes of novel common and rare variants. Functional annotation of risk alleles (single variants and combinations of alleles) in the large number of affected and unaffected family members, combined with the variation identified through the 1000 Genome Project, should accelerate identification of disease genes. This project will use and further develop high throughput genomic approaches for a combined analysis of genotypes and whole genome sequence that should be applicable to the analysis of other psychiatric disorders and studies of large families. The identification of etiological basis of bipolar disorder in a genetic isolate will shed light on the gene pathways that are involved in this disorder in the general population.

描述（由申请人提供）：双相情感障碍是一种终身的、经常复发的慢性精神疾病，通常出现在青年期，其特征是情绪波动，包括躁狂或轻躁狂和抑郁的复发性发作。双相情感障碍的终生患病率估计为1 - 3.7%，不幸的是，大约10-15%的受影响个体死于自杀。我们研究的一个长期目标是确定双相情感障碍的分子事件。为了补充正在进行的大规模全基因组关联研究，我们专注于一个非常大的阿米什家族，具有高发病率/患病率和发展双相情感障碍的风险，以确定常见和罕见的变异，单核苷酸多态性和结构变异与疾病易感性。我们建议将联合收割机高密度SNP基因分型（对所有个体）与下一代测序（对选定子集）相结合，以从对该遗传分离株遗传变异的完整理解中提取最大价值。为了实现这一目标，我们提出了一个三步策略：a）使用Illumina Omni2.5-Quad阵列为分离双相情感障碍家系中所有450个表型良好的家族成员建立高密度基因型图谱; B）通过60个个体的全基因组测序以无偏的方式产生全谱的遗传变体（20个亲子三人组），来自基因组学定义的亚家族，具有不同的疾病状态（受影响和未受影响）;和c）推断鉴定的突变谱（罕见的单核苷酸多态性和结构变异）到整个谱系，特别是具有重叠单倍型的未测序的家族成员，（Li等，2009; Howie等人，2010年）。 该变体插补将使用所有450名受试者可用的基因型平台上的SNP标记与通过深度测序鉴定的SNP之间的相关性，以预测新型常见和罕见变体的位置和基因型。在大量受影响和未受影响的家庭成员中对风险等位基因（单个变体和等位基因组合）的功能注释，结合通过1000个基因组计划鉴定的变异，应该加速疾病基因的鉴定。该项目将使用并进一步开发高通量基因组方法，用于基因型和全基因组序列的联合分析，这应适用于其他精神疾病的分析和大家族的研究。双相情感障碍遗传隔离的病因学基础的鉴定将揭示在一般人群中参与这种疾病的基因通路。