Calkins Monica E, Dobie Dorcas J, Cadenhead Kristin S, Olincy Ann, Freedman Robert, Green Michael F, Greenwood Tiffany A, Gur Raquel E, Gur Ruben C, Light Gregory A, Mintz Jim, Nuechterlein Keith H, Radant Allen D, Schork Nicholas J, Seidman Larry J, Siever Larry J, Silverman Jeremy M, Stone William S, Swerdlow Neal R, Tsuang Debby W, Tsuang Ming T, Turetsky Bruce I, Braff David L
Neuropsychiatry Section, Department of Psychiatry, University of Pennsylvania, 10 Gates, 3400 Spruce St, Philadelphia, PA 19104, USA.
Schizophr Bull. 2007 Jan;33(1):33-48. doi: 10.1093/schbul/sbl044. Epub 2006 Oct 11.
The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health-funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment.
The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database.
As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110).
Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia.
精神分裂症遗传学联盟（COGS）是一项正在进行的、由美国国立精神卫生研究所资助的、涉及7个研究点的合作项目，旨在调查与精神分裂症相关的定量内表型的发生情况及遗传结构。本文旨在描述COGS的结构和方法，包括参与者的招募和评估。
基于假设的招募策略确定的家庭包括：先证者符合《精神障碍诊断与统计手册》第四版精神分裂症诊断标准，且至少有一名未患病的同胞可用于基因分型和内表型分析，同时父母也可用于基因分型及（根据年龄而定）内表型分析。选择这样的家庭结构是为了在定量内表型特征上形成对比，从而最大化计划中的遗传分析效力。先证者从多个来源招募，包括临床医生转诊、当地精神疾病全国联盟分会以及媒体广告。所有参与者都要接受标准化方案，包括临床特征描述、采集血样用于基因分型以及内表型评估（P50抑制、前脉冲抑制、反扫视表现、连续作业任务、字母数字广度、言语记忆以及计算机化神经认知成套测验）。研究人员每周参加电话会议，以协调和评估招募、临床评估、内表型分析以及数据收集和分析的持续质量控制。通过使用一个高度质量保证的、基于网络的集中式数据库来维持数据完整性。
截至2006年2月，已招募355个家庭，688名参与者已完成内表型分析，包括精神分裂症先证者（n = 154，男：女 = 110：44）、一级生物学亲属（n = 343，男：女 = 151：192）以及社区对照对象（n = 191，男：女 = 81：110）。
成功的多研究点遗传学合作必须制定标准化的评估和招募方法标准，这些标准要明确界定、充分沟通并统一应用。同时，利用内表型的研究需要严格遵守跨研究点数据采集、设备校准和测试以及软件等效性的标准，并且要对跨研究点获得的许多测量指标进行持续质量保证。本报告描述了方法，并介绍了COGS的结构，作为多研究点内表型遗传学研究的一个模型。它还提供了头两年数据收集后的人口统计学信息，关于一个样本，其行为数据和内表型表现的遗传学将在未来的文章中进行全面描述。后续综述中讨论的一些问题反映了在精神分裂症内表型遗传结构研究中评估内表型的挑战。
