mRNA Sequencing Reveals Altered Synaptic Vesicular Transport in Post-Mortem Cerebellum

Schizophrenia (SCZ) is a common, disabling mental illness with high heritability but complex, poorly understood genetic etiology. As the first phase of a genomic convergence analysis of SCZ, we generated 16.7 billion nucleotides of short read, shotgun sequences of cDNA from post-mortem cerebellar cortices of 14 patients and six matched controls. A rigorous analysis pipeline was developed for analysis of digital gene expression studies. Sequences aligned to approximately 33,200 transcripts in each sample, with average coverage of 450 reads per gene. Following adjustments for confounding clinical, sample and experimental sources of variation, 215 genes differed significantly in expression between cases and controls. Golgi apparatus, vesicular transport, membrane association, Zinc binding and regulation of transcription were over-represented among differentially expressed genes. Twenty three genes with altered expression and involvement in presynaptic vesicular transport, Golgi function and GABAergic neurotransmission define a unifying molecular hypothesis for dysfunction in cerebellar cortex in SCZ.

精神分裂症（Schizophrenia, SCZ）是一种常见的致残性精神疾病，遗传力较高，但遗传病因复杂且尚未明确。作为精神分裂症基因组汇聚分析的首个阶段，我们对14名患者及6名匹配对照的死后小脑皮质的互补DNA（cDNA）进行了短读长鸟枪测序，共生成167亿核苷酸的测序数据。我们开发了一套严谨的分析流程，用于数字基因表达研究的分析。每个样本中的测序序列可比对至约33200个转录本，单个基因的平均测序覆盖度为450条读段（reads）。在对混杂的临床、样本及实验来源的变异因素进行校正后，病例组与对照组间共有215个基因的表达水平存在显著差异。差异表达基因中显著富集的功能类别包括高尔基体（Golgi apparatus）、囊泡运输、膜结合、锌结合以及转录调控。23个表达发生改变且参与突触前囊泡运输、高尔基体功能及γ-氨基丁酸能神经传递（GABAergic neurotransmission）的基因，共同构成了精神分裂症患者小脑皮质功能异常的统一分子假说。