Brain multi-omic Mendelian randomisation to identify novel drug targets for gliomagenesis.

IF 3.1 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Human molecular genetics Pub Date : 2024-11-20 DOI:10.1093/hmg/ddae168

Zak A Thornton, Lily J Andrews, Huiling Zhao, Jie Zheng, Lavinia Paternoster, Jamie W Robinson, Kathreena M Kurian

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Abstract

Background: Genetic variants associated with molecular traits that are also associated with liability to glioma can provide causal evidence for the identification and prioritisation of drug targets.

Methods: We performed comprehensive two-sample Mendelian randomisation (Wald ratio and/or IVW) and colocalisation analyses of molecular traits on glioma. Instrumentable traits (QTLs P < 5 × 10-8) were identified amongst 11 985 gene expression measures, 13 285 splicing isoforms and 10 198 protein abundance measures, derived from 15 brain regions. Glioma summary-level data was extracted from a genome-wide association meta-analysis of 12 496 cases and 18 190 controls.

Results: We found evidence for causal effect of 22 molecular traits (across 18 genes/proteins) on glioma risk. Thirteen molecular traits have been previously linked with glioma risk and five were novel; HBEGF (5q31.3) expression and all glioma [OR 1.36 (95%CI 1.19-1.55); P = 4.41 × 10-6]; a CEP192 (18p11.21) splice isoform and glioblastoma [OR 4.40 (95%CI 2.28-8.48); P = 9.78 × 10-4]; a FAIM (3q22.3) splice isoform and all glioma [OR 2.72-3.43; P = 1.03 × 10-5 to 1.09 × 10-5]; a SLC8A1 (2p22.1) splice isoform and all glioma [OR 0.37 (95%CI 0.24-0.56; P = 5.72 × 10-6]; D2HGDH (2q37.3) protein and all glioma [OR 0.86 (95%CI 0.80-0.92); P = 5.94 × 10-6)].

Conclusions: We provide robust causal evidence for prioritising genes and their protein products in glioma research. Our results highlight the importance of alternative splicing as a mechanism in gliomagenesis and as an avenue for exploration of drug targets.

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通过脑多组学孟德尔随机法确定胶质瘤发生的新型药物靶点。

背景：与胶质瘤易感性相关的分子特征的遗传变异可为药物靶点的识别和优先排序提供因果证据：我们对胶质瘤的分子性状进行了全面的双样本孟德尔随机化（Wald ratio和/或IVW）和共定位分析。方法：我们对胶质瘤的分子性状进行了全面的两样本孟德尔随机化（Wald ratio和/或IVW）和共定位分析：我们发现了 22 个分子性状（涉及 18 个基因/蛋白质）对胶质瘤风险具有因果效应的证据。其中 13 个分子性状与胶质瘤风险有关联，5 个是新的；HBEGF（5q31.3）表达与所有胶质瘤[OR 1.36（95%CI 1.19-1.55）；P = 4.41 × 10-6]；CEP192（18p11.21）剪接异构体与胶质母细胞瘤[OR 4.40（95%CI 2.28-8.48）；P = 9.78 × 10-4]；FAIM（3q22.3）剪接异构体与所有胶质瘤[OR 2.72-3.43; P = 1.03 × 10-5 to 1.09 × 10-5]；SLC8A1（2p22.1）剪接异构体与所有胶质瘤[OR 0.37 (95%CI 0.24-0.56; P = 5.72 × 10-6]；D2HGDH (2q37.3) 蛋白与所有胶质瘤[OR 0.86 (95%CI 0.80-0.92); P = 5.94 × 10-6)]：我们为胶质瘤研究中优先考虑基因及其蛋白产物提供了有力的因果证据。我们的研究结果凸显了替代剪接作为胶质瘤发生机制的重要性，以及作为探索药物靶点的途径的重要性。

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来源期刊

Human molecular genetics 生物-生化与分子生物学

CiteScore

6.90

自引率

2.90%

发文量

294

审稿时长

2-4 weeks

期刊介绍： Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include: the molecular basis of human genetic disease developmental genetics cancer genetics neurogenetics chromosome and genome structure and function therapy of genetic disease stem cells in human genetic disease and therapy, including the application of iPS cells genome-wide association studies mouse and other models of human diseases functional genomics computational genomics In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.