阳性和阴性症状的荟萃分析揭示了精神分裂症修饰基因。
Meta-analysis of Positive and Negative Symptoms Reveals Schizophrenia Modifier Genes.
作者信息
Edwards Alexis C, Bigdeli Tim B, Docherty Anna R, Bacanu Silviu, Lee Donghyung, de Candia Teresa R, Moscati Arden, Thiselton Dawn L, Maher Brion S, Wormley Brandon K, Walsh Dermot, O'Neill Francis A, Kendler Kenneth S, Riley Brien P, Fanous Ayman H
机构信息
Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA;
Department of Psychology and Neuroscience, University of Colorado, Boulder, CO; Institute for Behavioral Genetics, University of Colorado, Boulder, CO;
出版信息
Schizophr Bull. 2016 Mar;42(2):279-87. doi: 10.1093/schbul/sbv119. Epub 2015 Aug 27.
BACKGROUND
Evidence suggests that genetic factors may influence both schizophrenia (Scz) and its clinical presentation. In recent years, genome-wide association studies (GWAS) have demonstrated considerable success in identifying risk loci. Detection of "modifier loci" has the potential to further elucidate underlying disease processes.
METHODS
We performed GWAS of empirically derived positive and negative symptom scales in Irish cases from multiply affected pedigrees and a larger, independent case-control sample, subsequently combining these into a large Irish meta-analysis. In addition to single-SNP associations, we considered gene-based and pathway analyses to better capture convergent genetic effects, and to facilitate biological interpretation of these findings. Replication and testing of aggregate genetic effects was conducted using an independent European-American sample.
RESULTS
Though no single marker met the genome-wide significance threshold, genes and ontologies/pathways were significantly associated with negative and positive symptoms; notably, NKAIN2 and NRG1, respectively. We observed limited overlap in ontologies/pathways associated with different symptom profiles, with immune-related categories over-represented for negative symptoms, and addiction-related categories for positive symptoms. Replication analyses suggested that genes associated with clinical presentation are generalizable to non-Irish samples.
CONCLUSIONS
These findings strongly support the hypothesis that modifier loci contribute to the etiology of distinct Scz symptom profiles. The finding that previously implicated "risk loci" actually influence particular symptom dimensions has the potential to better delineate the roles of these genes in Scz etiology. Furthermore, the over-representation of distinct gene ontologies/pathways across symptom profiles suggests that the clinical heterogeneity of Scz is due in part to complex and diverse genetic factors.
背景
有证据表明遗传因素可能影响精神分裂症（Scz）及其临床表现。近年来，全基因组关联研究（GWAS）在识别风险位点方面取得了显著成功。检测“修饰位点”有可能进一步阐明潜在的疾病过程。
方法
我们对来自多重患病家系的爱尔兰病例以及一个更大的独立病例对照样本中根据经验得出的阳性和阴性症状量表进行了GWAS，随后将这些结果合并为一项大型爱尔兰荟萃分析。除了单核苷酸多态性（SNP）关联分析外，我们还考虑了基于基因和通路的分析，以更好地捕捉聚合遗传效应，并便于对这些发现进行生物学解释。使用一个独立的欧美样本对聚合遗传效应进行复制和检验。
结果
尽管没有单个标记达到全基因组显著性阈值，但基因以及本体/通路与阴性和阳性症状显著相关；值得注意的是，分别为NKAIN2和NRG1。我们观察到与不同症状特征相关的本体/通路存在有限的重叠，与阴性症状相关的免疫相关类别占比过高，而与阳性症状相关的成瘾相关类别占比过高。复制分析表明，与临床表现相关的基因可推广到非爱尔兰样本。
结论
这些发现有力地支持了修饰位点促成不同Scz症状特征病因的假说。先前涉及的“风险位点”实际上影响特定症状维度的这一发现，有可能更好地界定这些基因在Scz病因中的作用。此外，不同症状特征中不同基因本体/通路的过度表达表明，Scz的临床异质性部分归因于复杂多样的遗传因素。
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