Narayanan Balaji, Ethridge Lauren E, O'Neil Kasey, Dunn Sabra, Mathew Ian, Tandon Neeraj, Calhoun Vince D, Ruaño Gualberto, Kocherla Mohan, Windemuth Andreas, Clementz Brett A, Tamminga Carol A, Sweeney John A, Keshavan Matcheri S, Pearlson Godfrey D
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
Am J Psychiatry. 2015 May;172(5):466-78. doi: 10.1176/appi.ajp.2014.13101411. Epub 2015 Jan 23.
Biological risk factors underlying psychosis are poorly understood. Biological underpinnings of the dimension of psychosis can be derived using genetic associations with intermediate phenotypes such as subcomponents of auditory event-related potentials (ERPs). Various ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder are heritable and are expressed in unaffected relatives, although studies investigating genetic contributions to ERP abnormalities are limited. The authors used a novel parallel independent component analysis (para-ICA) to determine which empirically derived gene clusters are associated with data-driven ERP subcomponents, assuming a complex etiology underlying psychosis.
The authors examined the multivariate polygenic association of ERP subcomponents from 64-channel auditory oddball data in 144 individuals with schizophrenia, 210 psychotic bipolar disorder probands, and 95 healthy individuals from the multisite Bipolar-Schizophrenia Network on Intermediate Phenotypes study. Data were reduced by principal components analysis to two target and one standard ERP waveforms. Multivariate association of compressed ERP waveforms with a set of 20,329 single-nucleotide polymorphisms (SNPs) (reduced from a 1-million-SNP array) was examined using para-ICA. Genes associated with SNPs were further examined using pathway analysis tools.
Para-ICA identified four ERP components that were significantly correlated with three genetic components. Enrichment analysis revealed complement immune response pathway and multiple processes that significantly mediate ERP abnormalities in psychosis, including synaptic cell adhesion, axon guidance, and neurogenesis.
This study identified three genetic components comprising multiple genes mediating ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder. The data suggest a possible polygenic structure comprising genes influencing key neurodevelopmental processes, neural circuitry, and brain function mediating biological pathways plausibly associated with psychosis.
人们对精神病潜在的生物学风险因素了解甚少。精神病维度的生物学基础可以通过与诸如听觉事件相关电位（ERP）子成分等中间表型的基因关联来推导。精神分裂症和精神病性双相情感障碍中各种ERP子成分异常具有遗传性，并在未患病亲属中表现出来，尽管研究基因对ERP异常影响的研究有限。作者使用一种新颖的并行独立成分分析（para-ICA）来确定哪些根据经验得出的基因簇与数据驱动的ERP子成分相关，假设精神病存在复杂的病因。
作者在多中心中间表型双相情感障碍-精神分裂症网络研究中，检查了144名精神分裂症患者、210名精神病性双相情感障碍先证者和95名健康个体的64通道听觉oddball数据中ERP子成分的多变量多基因关联。通过主成分分析将数据简化为两个目标ERP波形和一个标准ERP波形。使用para-ICA检查压缩后的ERP波形与一组20329个单核苷酸多态性（SNP）（从100万个SNP阵列中减少）的多变量关联。使用通路分析工具进一步检查与SNP相关的基因。
Para-ICA识别出四个与三个遗传成分显著相关的ERP成分。富集分析揭示了补体免疫反应通路以及多个显著介导精神病中ERP异常的过程，包括突触细胞粘附、轴突导向和神经发生。
本研究确定了三个遗传成分，包括多个介导精神分裂症和精神病性双相情感障碍中ERP子成分异常的基因。数据表明可能存在一种多基因结构，包括影响关键神经发育过程、神经回路和脑功能的基因，这些基因介导了可能与精神病相关的生物学通路。
