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

基本信息

批准号：
8210461
负责人：
MAJA BUCAN
金额：
$ 101.64万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/8210461
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: This project will potentially reveal the genetic architecture of bipolar disorder using a novel approach that combines whole genome sequencing of selected family members from an extended Amish pedigree, with high-density SNP genotypes on a larger number of related family members. Common and rare genetic variants identified in this project may impact future development of therapies for bipolar and other related psychiatric disorders.

描述（由申请人提供）：双相情感障碍是一种终身，经常出现的慢性精神疾病，通常出现在年轻的成年中，其特征是情绪波动，包括躁狂症或躁狂症和抑郁症的复发性发作。双相情感障碍的终生患病率估计值为1-3.7％，悲惨地，大约10-15％的受影响的个体死于自杀。我们研究的一个长期目标是确定双相情感障碍构成的分子事件。为了补充正在进行的大规模基因组关联研究，我们专注于一个非常大的阿米什人家族，其发病率/患病率高以及患有躁郁症的风险，以鉴定常见和罕见的变异，单核苷酸多态性以及与疾病易感性相关的结构变异。我们建议将高密度SNP基因分型（在所有个体上）与下一代测序（在选定子集上）相结合，以从对该遗传分离物中遗传变异的完全理解中提取最大值。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 Questrays建立所有450个良好型家族成员的高密度基因型图； b）从基因组定义的亚科且具有不同的疾病状态（受影响和不受影响）的整个基因组测序中，以公正的方式通过整个基因组测序产生了全基因组测序的全谱。 c）将一系列鉴定的突变（罕见的单核苷酸多态性和结构变体）推断为整个谱系，特别是针对具有重叠单倍型重叠的未序列家庭成员，（Li等，2009; Howie等人，2010年）。这种变体的插补将使用可用于所有450名受试者的基因型平台上的SNP标记之间的相关性，并通过深层测序识别，以预测新型常见和稀有变体的位置和基因型。大量受影响和未受影响的家庭成员的风险等位基因（单个变体和等位基因组合）的功能注释，加上通过1000个基因组项目确定的变异，应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，用于对基因型和整个基因组序列的组合分析，该分析应适用于对其他精神疾病的分析和大型家庭的研究。遗传分离株中双相情感障碍的病因基础的鉴定将阐明一般人群中这种疾病所涉及的基因途径。公共卫生相关性：该项目将使用一种新颖的方法来揭示躁郁症的遗传结构，该方法结合了从扩展的Amish谱系中选定的家族成员的整个基因组测序，以及大量相关家庭成员的高密度SNP基因型。该项目中发现的常见和稀有的遗传变异可能会影响双极和其他相关精神疾病疗法的未来发展。