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：
8514076
负责人：
MAJA BUCAN
金额：
$ 87.54万
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/8514076
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 deep sequencing density family influence genetic linkage analysis genetic pedigree genetic variant genome sequencing genome wide association study hypomania interest member next generation sequencing 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.

描述（由申请人提供）：双相情感障碍是一种终生、经常反复发作的慢性精神疾病，通常出现在成年早期，其特征是情绪波动，包括反复发作的躁狂或轻躁狂和抑郁。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。我们研究的长期目标是确定双相情感障碍背后的分子事件。为了补充正在进行的大规模全基因组关联研究，我们重点关注一个异常大的阿米什家族，该家族具有高发病率/患病率和发展双相情感障碍的风险，以识别与疾病易感性相关的常见和罕见变异、单核苷酸多态性和结构变异。我们建议将高密度 SNP 基因分型（针对所有个体）与下一代测序（针对选定的子集）相结合，以从对该遗传分离株的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 阵列为双相情感障碍谱系中的所有 450 个表型良好的家庭成员建立高密度基因型图谱； b) 通过对来自基因组定义的亚科且具有不同疾病状态（受影响和未受影响）的 60 个个体（20 个亲子三人组）进行全基因组测序，以公正的方式生成全谱遗传变异； c) 推断整个谱系的一系列已识别突变（罕见的单核苷酸多态性和结构变异），特别是具有重叠单倍型的未测序家族成员（Li 等人，2009 年；Howie 等人，2010 年）。这种变异插补将利用所有 450 名受试者的基因型平台上的 SNP 标记与深度测序识别的 SNP 之间的相关性，来预测新的常见和罕见变异的位置和基因型。对大量受影响和未受影响的家庭成员中的风险等位基因（单个变异和等位基因组合）进行功能注释，结合通过千人基因组计划鉴定的变异，应该会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来对基因型和全基因组序列进行组合分析，该方法应适用于其他精神疾病的分析和大家庭的研究。在遗传分离株中鉴定双相情感障碍的病因学基础将有助于揭示普通人群中与该疾病相关的基因途径。