GENETICS OF BIPOLAR DISORDER IN LATINO POPULATIONS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：该项目的目标是收集来自385个拉丁裔家庭的诊断信息和DNA样本，每个家庭至少有两个兄弟姐妹患有BPI（DSM-IV诊断），以检测该人群中的BPI易感基因座。 通过与BPI相关的神经认知和结构MRI测试定义的内表型将在这些家系中进行验证，并且有助于这些生物变量的基因也将通过协变量定量性状分析进行映射。 研究方法：将在圣安东尼奥研究中心采集一部分受试者（来自约30个家庭）的成像数据，以验证作为内源性表型的结构成像指标。 我们将在四年的时间里每年为大约60名受试者（15名患有BPI的兄弟姐妹，30名未受影响的兄弟姐妹和15名对照）进行MRI检查。我们在获取BP受试者和对照者的MRI方面拥有丰富的经验，在过去两年中已对140例受试者进行了MRI检查。 我们将使用位于UTHSCSA研究成像中心（RIC）的GE/Elscint Prestige 2-T高场磁共振（MR）扫描仪。 扫描将由经过严格培训的MR技术人员进行。首先获得矢状面侦察序列，以验证患者位置、图像质量和大脑外侧裂导水管的完整范围的清晰度，从而定位中线矢状面图像。将在冠状面进行3D T1-FFE（T-1加权快速场回波），TR为25 ms，TE为5 ms，翻转角为40 o，视野（FOV）为240 mm x 220 mm，层厚为1.0 mm，NEX=2，矩阵大小为256 x 192，以获得覆盖整个大脑的图像。 我们还将使用自旋回波序列获得轴向平面的T2和质子密度图像，并筛选神经放射学异常。采集3D T1-FFE和自旋回波序列的总时间约为25分钟。 将根据先前发表的用于这些特定脑区域的解剖MRI测量的方法来识别和描绘所提议的感兴趣区域（ROI）。 将在3个解剖平面中识别解剖区域，参考标准解剖脑图谱，并将使用这些结构的三维体积渲染视图的检查来帮助识别边界。 所有形态测量将在Dr. Jair Soares的实验室中进行，由经过良好培训的评估者进行这些特定程序，并且这些特定测量的评估者间可靠性超过0.90。 将使用3D T1-FFE MRI数据和基于灰度、白色物质和脑脊液像素强度直方图生成的半自动分割方法估计脑ROI中的灰度和白色物质和脑脊液（CSF）的体积。 该方法使用直方图方法来确定分离灰质、白色物质和CSF的阈值，如先前描述的方法180、181、186、187。 对于60例受影响个体和60例健康对照受试者的拟定样本量，我们将有80%的把握度（1-B%）拒绝无效假设（a=0.05），即对于小效应量（最小效应量= 0.25）的对照，组间无差异。考虑到上文报告的前扣带回（效应量=1.08）和左杏仁核（效应量=0.64）的病例对照对比效应量，我们预计检测组间差异的把握度为96%至99.9%。 假设未受影响的亲属的体积测量值介于受影响和无关个体之间，有120名未受影响的家庭成员和60名健康对照受试者，我们预计检测组间差异的能力范围为59%至99.6%，具体取决于ROI。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The goal of this project is to collect diagnostic information and DNA samples from 385 families of Latino descent, each with a minimum of two siblings affected with BPI (DSM-IV diagnosis) in order to detect BPI susceptibility loci in this population. Endophenotypes defined by neurocognitive and structural MRI tests related to BPI will be validated in these pedigrees and genes which contribute to these biologic variables will also be mapped through covariate quantitative trait analyses. RESEARCH PLAN AND METHODS: Imaging data will be acquired for a subset of subjects (from approximately 30 families) at the San Antonio site in order to validate structural imaging measures as endophenotypes. We will obtain MRIs for approximately 60 subjects a year (15 siblings with BPI, 30 unaffected siblings, and 15 controls) over a four year period. We have extensive experience in obtaining these MRIs for BP subjects and controls and have done so for 140 subjects over the last two years. We will use a GE/Elscint Prestige 2-T high-field magnetic resonance (MR) scanner, located at the UTHSCSA Research Imaging Center (RIC). The scans will be performed by a highly trained MR technician. A sagittal scout series is first obtained to verify patient position, image quality, and clarity of the full extent of the aqueduct of sylvius to locate a midline sagittal image. 3D T1-FFE (T-1 weighted fast field echo) will be performed in the coronal plane with TR of 25 ms, TE of 5 ms, flip angle of 40o, field of view (FOV) 240 mm x 220 mm, slice thickness of 1.0 mm, NEX=2 and matrix size of 256x192, to obtain images covering the entire brain. We will additionally use a spin echo sequence to obtain T2 and proton density images in the axial plane and screen for neuroradiological abnormalities. The total time to collect the 3D T1-FFE and spin echo sequence is approximately 25 minutes. The proposed regions-of-interest (ROIs) will be identified and delineated according to previously published methods for anatomical MRI measurements of these particular brain regions. The anatomical regions will be identified in 3 anatomical planes, in reference to standard anatomical brain atlases, and examination of the three-dimensional volume-rendered view of these structures will be used to facilitate identification of boundaries. All morphometric measures will be performed in the laboratory of Dr. Jair Soares by raters well trained to do these specific procedures, and who have achieved inter-rater reliability of over 0.90 for these specific measurements. The volume of gray and white matter and cerebrospinal fluid (CSF) in the brain ROIs will be estimated using the 3D T1-FFE MRI data and a semi-automated segmentation method based on the generation of histogram of gray, white matter and cerebrospinal fluid pixel intensities. This method uses a histogram approach to determine the thresholds for separation of gray matter, white matter, and CSF, as per method previously described 180,181186,187. With the proposed sample size of 60 affected individuals and 60 healthy comparison subjects, we will have 80% power (1-b%) to reject the null hypothesis (a=0.05) of no between group difference for a contrast with small effect size (minimum effect size = 0.25). Given the effect sizes of case-control contrast for the anterior cingulate (effect size=1.08) and left amygdala (effect size=0.64) reported above, we anticipate power to detect between group differences to vary from 96 to 99.9%. Assuming that volumetric measurements for unaffected relatives are midway between affected and unrelated individuals, with 120 unaffected family members and 60 healthy comparison subjects, we anticipate power to detect between group differences to range from 59 to 99.6%, depending on the ROI.