Genomic analysis of bipolar disorder in a genetic isolate

描述（由申请人提供）：双相情感障碍是一种终身的，经常反复发作的慢性精神疾病，通常出现在青年期，其特征是情绪波动，包括反复发作的躁狂或轻躁狂和抑郁症。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%的患者死于自杀。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，我们重点研究了一个具有高发病率/患病率和发展为双相情感障碍风险的特大Amish家族，以确定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（对所有个体）与下一代测序（对选定的子集）相结合，以从对该遗传分离物的遗传变异的全面了解中提取最大价值。为了实现这一目标，我们提出了三步策略：a)使用Illumina Omni2.5-Quad阵列建立分离双相情感障碍谱系中所有450个表型良好的家族成员的高密度基因型图谱；B)通过对来自基因组定义的亚家族和不同疾病状态（受影响和未受影响）的60个人（20个亲子三人组）进行全基因组测序，以公正的方式产生全谱遗传变异；c)推断出整个谱系中已确定的突变（罕见的单核苷酸多态性和结构变异）的谱，特别是包含重叠单倍型的未测序家庭成员（Li et al., 2009; Howie et al., 2010）。这种变异归算将利用所有450名受试者基因型平台上的SNP标记与深度测序鉴定的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。大量患病和未患病家庭成员的风险等位基因（单变异体和等位基因组合）的功能注释，结合通过1000基因组计划鉴定的变异，应能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综合分析，这应该适用于其他精神疾病的分析和大家庭的研究。在遗传分离物中确定双相情感障碍的病因学基础将阐明在一般人群中参与这种疾病的基因途径。

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.