High Density Genome Wide Linkage Analysis of 922 Bipolar Families

描述（申请人提供）：从1988年到2003年，NIMH遗传学倡议支持了699个多重双相情感障碍家庭的确定和银行。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位点提供了统计学上显著的证据，但与精神分裂症相比，双相情感障碍的基因定位研究产生的结果较少。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使用更多家族和更高密度的DMA标记（~ 4cM或更少）进行更大规模的连锁研究。到目前为止，大多数连锁研究平均只有-50至250个家庭，显然是不够有力的。此外，这些家庭的基因分型，其中许多是缺失巴伦支的同胞对，使用微卫星间隔仅为每10厘米。大多数研究的遗传信息含量为0.6或更少。理论和经验数据表明，更高密度的基因分型更大的样本的家庭将是值得的，特别是如果集中在一个种族群体。为了收集这一独特的和统计上强大的样本，我们将首先选择分析665个欧洲高加索家庭目前可在NIMH库。其次，我们将在这个样本中添加257个额外的非存储库欧洲高加索家庭，这些家庭以前由雷·德保罗、弗朗西斯·麦克马洪、吉米·波塔什、艾略特·格申、约翰·凯尔索、道格拉斯黑木和威廉·拜尔利收集。922个家庭包含1，840例BPI障碍或SA-BP（占BPI总数的4%），327例BPI受试者和810例复发性抑郁症患者。共有2，977例受影响病例。遗传疾病研究中心（CIDR）已批准使用6 K Illumina光学微珠阵列对所有922个家庭（约6，000名受试者）进行基因分型。功效分析表明，在lod > 3.0时，我们有80%的功效检测到与至少1.2的paths的关联。将进行参数和非参数联系分析。建议第二年在其他小组以前没有确定的一到两个联系区域进行精细绘图研究。我们估计，NIMH已经投资了超过2000万美元的直接成本，用于收集这些家庭。拟议的研究将充分发挥NIMH的投资。

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.