High Density Genome Wide Linkage Analysis of 922 Bipolar Families

922 个双相家庭的高密度基因组全连锁分析

• 批准号: 7211626
• 负责人: William Byerley
• 金额: $ 21.13万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211626
• 关键词: Affect; Am 80; Appendix; Area; Bipolar Disorder; Caucasians; Caucasoid Race; Charge; Chromosome Mapping; Collection; Computer software; Critiques; Data; Depressive disorder; Direct Costs; Disease; Ethnic group; European; Extended Family; Family; Genetic; Genotype; Grant; Hand; Individual; Inherited; Investments; Letters; Major Depressive Disorder; Maps; Methods; Microsatellite Repeats; Modeling; Molecular; Molecular Genetics; National Institute of Mental Health; Neurofibromin 2; Numbers; Optics; Patient Self-Report; Play; Population; Population Group; Potassium Hydroxide; Recurrence; Research; Sampling; Schizophrenia; Series; Signal Transduction; Statistically Significant; Stratification; Structure; Work; affection; base; case control; density; experience; genetic linkage analysis; genetic pedigree; genome wide association study; genome-wide linkage; repository

DESCRIPTION (provided by applicant): From 1988 to 2003 the NIMH Genetics Initiative supported the ascertainment and banking of 699 multiplex bipolar families. Genome wide linkage analyses of these families have yielded statistically significant evidence for a few disease predisposing loci but in contrast to schizophrenia, gene- mapping studies of bipolar disorder have produced fewer findings. While genome wide association studies will soon come into play, there are a number of compelling reasons to support larger scale linkage studies with additional families and a higher density of DMA markers (-4 cM or less). To date, most linkage studies have averaged only -50 to 250 families and were obviously underpowered. Moreover, genotyping of these families, many of which were sib pairs with missing Barents, was carried out using microsatellites spaced only every -10 cMs. Genetic information content was .6 or less for most studies. Theoretical and empirical data indicate higher density genotyping of a larger sample of families will be worthwhile, especially if focused on one ethnic group. In order to assemble this unique and statistically powerful sample we will first select for analyses the 665 European Caucasian families currently available in the NIMH repository. Second, we will add to this sample 257 additional non-repository European Caucasian families previously collected by Ray Depaulo, Francis McMahon, Jimmy Potash, Eliot Gershon, John Kelsoe, Douglas Blackwood and William Byerley. The 922 families contain 1,840 cases of BPI disorder or SA-BP (4 percent of BPI total), 327 subjects with BPI and 810 individuals with Recurrent Depressive Disorder. All together there are 2,977 affected cases. The Center for Inherited Disease Research (CIDR) has approved genotyping of all 922 families (~6,000 subjects) with the 6K Illumina optical bead array. Power analysis indicates that we have 80 percent power at lod > 3.0 to detect linkage to lambdas of at least 1.2. Parametric and non-parametric linkage analyses will be carried out. Fine mapping studies are proposed for year 2 in one to two linkage regions not previously identified by other groups. All together we estimate that NIMH has invested over $20 million in direct costs just for the collection of these families. The proposed study will fully maximize the NIMH investment.

描述(由申请人提供)：从1988年到2003年，NIMH遗传学倡议支持了699个多重双相家庭的确定和保存。对这些家族的全基因组连锁分析已经为一些疾病易感基因产生了统计上有意义的证据，但与精神分裂症相比，双相情感障碍的基因图谱研究产生的发现较少。虽然全基因组关联研究将很快发挥作用，但有许多令人信服的理由支持更大规模的连锁研究，包括更多的家系和更高密度的DMA标记(-4 cM或更少)。到目前为止，大多数连锁研究平均只有50到250个家庭，显然动力不足。此外，对这些家系进行了基因分型，其中许多是Barent缺失的同胞对，使用的是每隔10个CMS才间隔的微卫星。在大多数研究中，遗传信息含量为0.6或更少。理论和经验数据表明，在更大的家庭样本中进行更高密度的基因分型将是值得的，特别是如果专注于一个种族群体。为了收集这个独特的、统计上强大的样本，我们将首先选择NIMH储存库中目前可用的665个欧洲高加索家庭进行分析。其次，我们将在这个样本中添加另外257个先前由Ray DePaulo、Francis McMahon、Jimmy Potash、Eliot Gershon、John Kelsoe、Douglas Blackwood和William Byerley收集的非存储库欧洲高加索家庭。这922个家庭包括1840例BPI障碍或SA-BP(占BPI总数的4%)，327名BPI受试者和810名复发性抑郁障碍患者。总共有2977例受影响的病例。遗传病研究中心(CIDR)已批准使用6K Illumina光学珠阵对所有922个家庭(约6,000名受试者)进行基因分型。功率分析表明，在Lod&gt；3.0，我们有80%的功率来检测与Lambdas至少1.2的链接。将进行参数和非参数链接分析。建议在第二年对以前没有被其他组确定的一到两个连锁区进行精细作图研究。我们估计，仅为收集这些家庭，NIMH已经投入了超过2000万美元的直接成本。拟议的研究将充分实现NIMH投资的最大化。