Genome-wide Association of Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia (COGS) Study
Genome-wide Association of Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia (COGS) Study
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DOI：
10.1001/jamapsychiatry.2019.2850
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发表时间：
2019-12-01
期刊：
影响因子：
25.8
通讯作者：
Braff, David L.
中科院分区：
文献类型：
--
作者：
Greenwood, Tiffany A.;Lazzeroni, Laura C.;Braff, David L.
这项全基因组关联研究报告了精神分裂症遗传学联盟 (COGS) 研究人群中精神分裂症患者和健康对照参与者的独立队列中的 11 种与精神分裂症相关的内表型。 精神分裂症作为探索潜在神经回路和遗传结构的平台。许多内表型与精神分裂症的功能不良结果相关。其中一些还被美国食品和药物管理局认可为潜在的治疗目标。目的 通过报告对精神分裂症独立 2 期 (COGS-2) 患者和健康对照参与者 (HCP) 队列中 11 种精神分裂症相关内表型的全基因组关联研究 (GWAS)，建立在 COGS 1 期 (COGS-1) 家族遗传性、关联性和连锁性的先前评估的基础上。设计、背景和参与者 通过 COGS 站点的协作，总共招募了 1789 名自我报告的欧洲或拉丁裔血统的精神分裂症患者和 HCP，并使用 PsychChip 进行基因分型。应用标准质量控制过滤器，插补后可获得超过 620 万个基因分型检出率大于 0.99 的变体。使用线性回归对按诊断和血统分层的数据集进行关联，并调整年龄、性别和 5 个主成分，并通过加权荟萃分析合并结果。 COGS-1的数据收集于2003年1月6日至2008年8月6日； COGS-2的数据，从2010年6月30日到2014年2月14日。数据从2016年10月28日到2018年5月4日进行分析。主要结果和措施进行了全基因组关联研究，以评估针对与抑制、注意力、警觉、学习、工作相关的精神分裂症关键领域的11种神经生理学和神经认知内表型的关联记忆、执行功能、情景记忆、 和社会认知。结果 1533 名参与者的最终样本包括 861 名男性参与者 (56.2%)，平均 (SD) 年龄为 41.8 (13.6) 岁。总共，7 个内表型的 7 个全基因组显着区域 (P < 5 x 10(-8)) 和 2 个近显着区域 (P < 9 x 10(-8)) 包含几个感兴趣的基因，包括 NRG3 和 HCN1。对于 11 种内表型中的每一种，在 P < 10(-4) 水平上进行的富集分析与 COGS-1 家族中先前的关联结果相比，表现出良好的结果，并显示与精神分裂症诊断所确定的区域有广泛的重叠。结论和相关性这些分析确定了几个需要进一步探索和验证的感兴趣的基因组区域。这些数据似乎证明了内表型在解决精神分裂症的遗传结构和表征潜在的生物功能障碍方面的效用。了解这些内表型的分子基础可能有助于确定新的治疗靶点，并为精神分裂症和相关精神障碍的精准医学铺平道路。问题：神经生理学和神经认知内表型的全基因组关联研究能否识别与精神分裂症潜在分子功能障碍相关的基因？研究结果 共有 7 个区域超过了传统的全基因组显着性阈值 (P < 5 x 10(-8))，与各种内表型缺陷相关，这些区域内的基因很大程度上涉及谷氨酸和轴突功能障碍以及其他神经生物学显着靶标。确定了许多感兴趣的区域，其中包括 39 个先前与精神分裂症诊断相关的区域。意义 这些结果表明，在基因组研究中使用定量内表型可能为理解精神分裂症的分子基础提供一种重要的、强有力的基于推理的策略，并可能提出新的治疗目标。
This genome-wide association study reports 11 schizophrenia-related endophenotypes in an independent cohort of patients with schizophrenia and healthy comparison participants within the Consortium on the Genetics of Schizophrenia study population.Importance The Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration. Objective To build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs). Design, Setting, and Participants A total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018. Main Outcomes and Measures A genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition. Results The final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P < 5 x 10(-8)) and 2 nearly significant regions (P < 9 x 10(-8)) containing several genes of interest, including NRG3 and HCN1, were identified for 7 endophenotypes. For each of the 11 endophenotypes, enrichment analyses performed at the level of P < 10(-4) compared favorably with previous association results in the COGS-1 families and showed extensive overlap with regions identified for schizophrenia diagnosis. Conclusions and Relevance These analyses identified several genomic regions of interest that require further exploration and validation. These data seem to demonstrate the utility of endophenotypes for resolving the genetic architecture of schizophrenia and characterizing the underlying biological dysfunctions. Understanding the molecular basis of these endophenotypes may help to identify novel treatment targets and pave the way for precision-based medicine in schizophrenia and related psychotic disorders.Question Can a genome-wide association study of neurophysiological and neurocognitive endophenotypes identify genes related to the underlying molecular dysfunctions in schizophrenia? Findings A total of 7 regions exceeding a conventional genome-wide significance threshold (P < 5 x 10(-8)) were associated with various endophenotype deficits, and the genes within these regions largely implicate glutamate and axonal dysfunctions as well as other neurobiologically salient targets. Many regions of interest were identified, including 39 previously associated with a schizophrenia diagnosis. Meaning These results suggest that the use of quantitative endophenotypes in genomic studies may provide an important, strong inference-based strategy for understanding the molecular basis of schizophrenia and may suggest novel treatment targets.