一种新颖的整合多组学方法，用于揭示罕见疾病的遗传决定因素及其在窦状隙阻塞综合征中的应用。
A novel integrative multi-omics approach to unravel the genetic determinants of rare diseases with application in sinusoidal obstruction syndrome.
机构信息
Institute of Social and Preventive Medicine, Childhood Cancer Research Group, University of Bern, Bern, Switzerland.
Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, CANSEARCH Research Platform in Pediatric Oncology and Hematology, University of Geneva, Geneva, Switzerland.
出版信息
PLoS One. 2023 Apr 5;18(4):e0281892. doi: 10.1371/journal.pone.0281892. eCollection 2023.
BACKGROUND
Genotype-phenotype analyses of rare diseases often suffer from a lack of power, due to small sample size, which makes identifying significant associations difficult. Sinusoidal obstruction syndrome (SOS) of the liver is a rare but life-threatening complication of hematopoietic stem cell transplantation (HSCT). The alkylating agent busulfan is commonly used in HSCT and known to trigger SOS. We developed a novel pipeline to identify genetic determinants in rare diseases by combining in vitro information with clinical whole-exome sequencing (WES) data and applied it in SOS patients and controls.
METHODS
First, we analysed differential gene expression in six lymphoblastoid cell lines (LCLs) before and after incubation with busulfan. Second, we used WES data from 87 HSCT patients and estimated the association with SOS at the SNP and the gene levels. We then combined the results of the expression and the association analyses into an association statistic at the gene level. We used an over-representation analysis to functionally characterize the genes that were associated with a significant combined test statistic.
RESULTS
After treatment of LCLs with busulfan, 1708 genes were significantly up-, and 1385 down-regulated. The combination of the expression experiment and the association analysis of WES data into a single test statistic revealed 35 genes associated with the outcome. These genes are involved in various biological functions and processes, such as "Cell growth and death", "Signalling molecules and interaction", "Cancer", and "Infectious disease".
CONCLUSIONS
This novel data analysis pipeline integrates two independent omics datasets and increases statistical power for identifying genotype-phenotype associations. The analysis of the transcriptomics profile of cell lines treated with busulfan and WES data from HSCT patients allowed us to identify potential genetic contributors to SOS. Our pipeline could be useful for identifying genetic contributors to other rare diseases where limited power renders genome-wide analyses unpromising.
TRIAL REGISTRATION
For the clinical dataset: Clinicaltrials.gov: NCT01257854. https://clinicaltrials.gov/ct2/history/NCT01257854.
背景
由于样本量小，罕见病的基因型-表型分析往往缺乏统计学效力，这使得确定显著相关性变得困难。肝窦阻塞综合征（SOS）是造血干细胞移植（HSCT）的一种罕见但危及生命的并发症。烷化剂白消安通常用于 HSCT，并已知会引发 SOS。我们开发了一种新的管道，通过将体外信息与临床全外显子组测序（WES）数据相结合，来鉴定罕见疾病的遗传决定因素，并将其应用于 SOS 患者和对照者。
方法
首先，我们分析了在 6 个淋巴母细胞系（LCL）中孵育白消安前后的差异基因表达。其次，我们使用了 87 名 HSCT 患者的 WES 数据，并估计了与 SOS 的 SNP 和基因水平的关联。然后，我们将表达和关联分析的结果结合到基因水平的关联统计中。我们使用过度表现分析来对与显著联合测试统计相关的基因进行功能特征化。
结果
在 LCL 中用白消安处理后，有 1708 个基因显著上调，有 1385 个基因下调。将表达实验和 WES 数据的关联分析结合成一个单一的测试统计，揭示了 35 个与结果相关的基因。这些基因参与了各种生物学功能和过程，如“细胞生长和死亡”、“信号分子和相互作用”、“癌症”和“传染病”。
结论
这种新的数据分析管道整合了两个独立的组学数据集，增加了识别基因型-表型关联的统计效力。对用白消安处理的细胞系的转录组学分析和 HSCT 患者的 WES 数据的分析，使我们能够识别 SOS 的潜在遗传贡献者。我们的管道可能对其他罕见疾病的遗传贡献者的识别有用，在这些疾病中，有限的效力使全基因组分析变得不那么有希望。
试验注册
对于临床数据集：Clinicaltrials.gov：NCT01257854。https://clinicaltrials.gov/ct2/history/NCT01257854。
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