通路分析表明神经胶质细胞与精神分裂症有关。
Pathway analyses implicate glial cells in schizophrenia.
作者信息
Duncan Laramie E, Holmans Peter A, Lee Phil H, O'Dushlaine Colm T, Kirby Andrew W, Smoller Jordan W, Öngür Dost, Cohen Bruce M
机构信息
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America ; Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America ; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States of America.
MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, United Kingdom.
出版信息
PLoS One. 2014 Feb 24;9(2):e89441. doi: 10.1371/journal.pone.0089441. eCollection 2014.
BACKGROUND
The quest to understand the neurobiology of schizophrenia and bipolar disorder is ongoing with multiple lines of evidence indicating abnormalities of glia, mitochondria, and glutamate in both disorders. Despite high heritability estimates of 81% for schizophrenia and 75% for bipolar disorder, compelling links between findings from neurobiological studies, and findings from large-scale genetic analyses, are only beginning to emerge.
METHOD
Ten publically available gene sets (pathways) related to glia, mitochondria, and glutamate were tested for association to schizophrenia and bipolar disorder using MAGENTA as the primary analysis method. To determine the robustness of associations, secondary analyses were performed with: ALIGATOR, INRICH, and Set Screen. Data from the Psychiatric Genomics Consortium (PGC) were used for all analyses. There were 1,068,286 SNP-level p-values for schizophrenia (9,394 cases/12,462 controls), and 2,088,878 SNP-level p-values for bipolar disorder (7,481 cases/9,250 controls).
RESULTS
The Glia-Oligodendrocyte pathway was associated with schizophrenia, after correction for multiple tests, according to primary analysis (MAGENTA p = 0.0005, 75% requirement for individual gene significance) and also achieved nominal levels of significance with INRICH (p = 0.0057) and ALIGATOR (p = 0.022). For bipolar disorder, Set Screen yielded nominally and method-wide significant associations to all three glial pathways, with strongest association to the Glia-Astrocyte pathway (p = 0.002).
CONCLUSIONS
Consistent with findings of white matter abnormalities in schizophrenia by other methods of study, the Glia-Oligodendrocyte pathway was associated with schizophrenia in our genomic study. These findings suggest that the abnormalities of myelination observed in schizophrenia are at least in part due to inherited factors, contrasted with the alternative of purely environmental causes (e.g. medication effects or lifestyle). While not the primary purpose of our study, our results also highlight the consequential nature of alternative choices regarding pathway analysis, in that results varied somewhat across methods, despite application to identical datasets and pathways.
背景
对精神分裂症和双相情感障碍神经生物学的探索仍在继续，多条证据表明这两种疾病中胶质细胞、线粒体和谷氨酸存在异常。尽管精神分裂症的遗传度估计高达81%，双相情感障碍为75%，但神经生物学研究结果与大规模基因分析结果之间令人信服的联系才刚刚开始显现。
方法
使用MAGENTA作为主要分析方法，对10个与胶质细胞、线粒体和谷氨酸相关的公开可用基因集（通路）进行精神分裂症和双相情感障碍的关联测试。为了确定关联的稳健性，使用ALIGATOR、INRICH和Set Screen进行了二次分析。所有分析均使用精神疾病基因组学联盟（PGC）的数据。精神分裂症有1,068,286个单核苷酸多态性（SNP）水平的p值（9,394例/12,462例对照），双相情感障碍有2,088,878个SNP水平的p值（7,481例/9,250例对照）。
结果
根据主要分析（MAGENTA p = 0.0005，单个基因显著性要求为75%），在进行多重检验校正后，胶质细胞-少突胶质细胞通路与精神分裂症相关，并且在INRICH（p = 0.0057）和ALIGATOR（p = 0.022）分析中也达到了名义显著性水平。对于双相情感障碍，Set Screen对所有三种胶质细胞通路均产生了名义上和全方法范围内的显著关联，与胶质细胞-星形胶质细胞通路的关联最强（p = 0.002）。
结论
与其他研究方法在精神分裂症中发现的白质异常结果一致，在我们的基因组研究中，胶质细胞-少突胶质细胞通路与精神分裂症相关。这些发现表明，精神分裂症中观察到的髓鞘形成异常至少部分归因于遗传因素，这与纯粹环境原因（如药物作用或生活方式）的观点形成对比。虽然不是我们研究的主要目的，但我们的结果也突出了通路分析中不同选择的重要性，因为尽管应用于相同的数据集和通路，但不同方法的结果仍存在一定差异。
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