Background

The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach.

Methods

FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold.

Results

We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed.

Conclusions

We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

中文翻译：

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跨多种组织类型的基因表达插补有助于深入了解额颞叶痴呆及其临床亚型的遗传结构

背景

额颞叶痴呆（FTD）的病因知之甚少。为了识别与 FTD 相关的预测表达水平的基因，我们使用转录组范围的关联研究方法将汇总统计数据与外部参考基因表达数据相结合。

方法

FUSION 软件用于利用 FTD 汇总统计数据（所有 FTD：n  = 2154 例，n  = 4308 对照；行为变异 FTD：n  = 1337 例，n  = 2754 对照；语义痴呆：n  = 308 例，n  = 616 对照；进行性非流畅性失语症：n  = 269 例，n  = 538 名对照；患有运动神经元疾病的 FTD：n  = 200 例，n  = 400 名对照）来自国际 FTD-基因组学联盟，具有 53 个表达定量基因座组织类型面板（n  = 12,205； 5 个财团）。使用 5% 的错误发现率阈值评估显着性。

结果

我们确定了 FTD 的 73 个重要基因-组织关联，代表 34 种组织类型中的 44 个独特基因。最重要的发现来自背外侧前额叶皮层剪接数据（n  = 19 个基因，26%）。17q21.31 倒位基因座包含 23 个显着关联，代表 6 个独特基因。其他热门歌曲包括SEC22B（一种参与囊泡运输的基因）、TRGV5和ZNF302。观察到行为变异 FTD的单个基因发现 ( RAB38 )。对于其他临床亚型，未观察到显着关联。

结论

我们确定了 FTD 的新候选基因（例如SEC22B）和先前报道的风险区域（例如 17q21.31）。尽管该参考面板的样本量适中，但在背外侧前额叶皮层剪接数据中观察到最显着的关联。这表明我们的研究结果是 FTD 特有的，并且可能是导致疾病病理学的不同 FTD 风险位点基因的生物学相关亮点。