The Bipolar Genome Study

描述（由申请人提供）：双相情感障碍（BD）是一种严重的精神疾病，影响1-3%的人口。尽管家庭和双胞胎研究支持强大的遗传性，但在识别特定基因方面进展缓慢。我们的联盟研究双相情感障碍的遗传学已有20多年，并收集了世界上最大的双相情感障碍家庭和病例样本之一。尽管全基因组关联研究（GWAS）已经确定了一些基因和重要的多基因成分，但这些定位方法仅取得了有限的成功。有人提出，这种“缺失的遗传能力”部分是通过大量具有强烈遗传效应的罕见变异来传递的。这些罕见变异的频率范围可能从不常见（<1%）到极其罕见（私人突变），并且可能包括多种类型，包括snp， indel和cnv。即使使用下一代芯片，GWAS检测这种罕见变异的能力也有限，而且外显子组测序遗漏了许多结构变异。幸运的是，在过去几年中，下一代测序技术以惊人的速度发展，使全基因组测序成为一种实用且负担得起的工具。我们建议利用我们收集的大量双相情感障碍家庭和我们的联盟最近进行的一项大型连锁研究，结合全基因组测序和靶向测序，来确定在双相情感障碍中起致病作用的强效罕见变异。利用我们最近的连锁研究，我们已经确定了52个有强烈关联证据的家庭，并从每个家庭中选择了一个最有可能携带致病变异的成员。在目标1中，我们将对这52名受试者的整个基因组进行测序，以确定在每个病例中有关联证据的基因组区域中具有强效应的罕见变异；总共12个区域。将在每个家庭的bet联动区域寻找预测的强功能效应的变体。在Aim 2中，这些候选的功能性罕见变异将通过Sanger测序进行验证，并检查其与家族疾病的共分离。在Aim 3中，这些变异将用于选择候选基因的优先列表，然后在1500例BD病例和1500例对照样本中进行靶向测序。我们假设，在那些传递双相障碍遗传易感性的基因中，将发现具有强大功能效应的其他罕见变异。我们将使用复杂的崩溃变异集分析方法来验证这一假设，即与对照组相比，这些基因在双相障碍病例中携带了更大的突变负担。所有测序数据将提供给科学界，并将为未来的研究提供宝贵的资源。识别

DESCRIPTION (provided by applicant): Bipolar disorder (BD) is a serious psychiatric disorder affecting 1-3% of the population. Though family and twin studies support strong heritability, progress towards identifying specific genes has been slow. Our consortium has studied the genetics of bipolar disorder for over 20 years, and collected one of the largest samples of bipolar families and cases in the world. Though genomewide association studies (GWAS) have identified some genes and a significant polygenic component, these mapping approaches have had only limited success. It has been proposed that this "missing heritability" is transmitted in part through a large number of rare variants of strong genetic effect. Such rare variants might range in frequency from uncommon (<1%) to extremely rare (private mutations), and may include a variety of types including SNPs, indels and CNVs. GWAS, even with next-generation chips, would have limited power to detect such rare variation, and exome sequencing misses many structural variants. Fortunately, next generation sequencing technology has advanced at a staggering pace in the last few years, making whole genome sequencing a practical and affordable tool. We propose to make use of our large collection of families with bipolar disorder and a recent large linkage study conducted by our consortium, in combination with whole genome sequencing and targeted sequencing, to identify rare variants of strong effect that play a causative role in BD. Using our recent linkage study, we have identified 52 families with strong evidence for linkage and selected one member from each family most likely to harbor causative variants. In Aim 1, we will sequence the entire genome of these 52 subjects in order to identify rare variants of strong effect in the genomic regions in each case for which there is evidence of linkage; 12 regions in all. Variants of predicted strong functional effect will be sought in the bet linkage region for each family. In Aim 2, these candidate functional rare variants will be validated by Sanger sequencing and examined for cosegregation with disease in their family. In Aim 3, these variants will be used to select a prioritized list of candidate genes that will then undergo targeted sequencing in a sample of 1,500 BD cases and 1,500 controls. We hypothesize that additional rare variants of strong functional effect will be identified in those genes that convey genetic vulnerability to BD. We will use a sophisticated collapsed variant set analysis approach to test the hypothesis that these genes carry a greater mutational burden in the BD cases as compared to controls. All sequencing data will be made available to the scientific community and will provide an invaluable resource for future studies. The identification of vulnerability genes and mutations in BD will contribute to our understanding of its biological mechanism and facilitate the development of new treatments.