对转录组和蛋白质组广泛关联研究的综合分析确定了肥胖症功能基因的优先次序。

IF 3.8 2区生物学 Q2 GENETICS & HEREDITY

Human Genetics Pub Date : 2024-11-04 DOI:10.1007/s00439-024-02714-w

Qi-Gang Zhao, Xin-Ling Ma, Qian Xu, Zi-Tong Song, Fan Bu, Kuan Li, Bai-Xue Han, Shan-Shan Yan, Lei Zhang, Yuan Luo, Yu-Fang Pei

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引用次数: 0

摘要

背景：全基因组关联研究发现了数十个肥胖基因组位点。然而，这些位点背后的功能基因及其详细的遗传机制却主要不为人知。在本研究中，我们进行了一项综合研究，通过结合全基因组、全转录组和全蛋白组关联分析的信息，对可能的功能基因进行优先排序：我们首先对六个肥胖相关性状进行了全蛋白质组关联分析和全转录组关联分析。然后，我们对在蛋白质组和转录物组关联分析中发现的共享基因座进行了共定位分析。最后，我们用其他血浆/血液参考面板验证了已确定的基因。我们还对高亮基因在其他组织中的表达、单细胞和组织特异性以及可药用性进行了评估：通过蛋白质组关联研究、转录组关联研究和共定位分析，我们优先确定了4个高置信度基因（FASN、ICAM1、PDCD6IP和YWHAB），它们在mRNA和蛋白质水平上一致影响着肥胖性状的变化。这 4 个基因已通过其他血浆/血液参考面板成功验证。这4个基因在肥胖相关组织中具有共同的调控结构。单细胞和组织特异性分析表明，FASN和ICAM1在代谢和免疫相关的组织和细胞中明确表达。此外，FASN 和 ICAM1 已被开发为药物靶点：我们的研究为肥胖症的进一步机理和治疗研究提供了新的有前景的蛋白靶点。

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Integrative analysis of transcriptome and proteome wide association studies prioritized functional genes for obesity.

Background: Genome-wide association studies have identified dozens of genomic loci for obesity. However, functional genes and their detailed genetic mechanisms underlying these loci are mainly unknown. In this study, we conducted an integrative study to prioritize plausibly functional genes by combining information from genome-, transcriptome- and proteome-wide association analyses.

Methods: We first conducted proteome-wide association analyses and transcriptome-wide association analyses for the six obesity-related traits. We then performed colocalization analysis on the identified loci shared between the proteome- and transcriptome-association analyses. Finally, we validated the identified genes with other plasma/blood reference panels. The highlighted genes were assessed for expression of other tissues, single-cell and tissue specificity, and druggability.

Results: We prioritized 4 high-confidence genes (FASN, ICAM1, PDCD6IP, and YWHAB) by proteome-wide association studies, transcriptome-wide association studies, and colocalization analyses, which consistently influenced the variation of obesity traits at both mRNA and protein levels. These 4 genes were successfully validated using other plasma/blood reference panels. These 4 genes shared regulatory structures in obesity-related tissues. Single-cell and tissue-specific analyses showed that FASN and ICAM1 were explicitly expressed in metabolism- and immunity-related tissues and cells. Furthermore, FASN and ICAM1 had been developed as drug targets.

Conclusion: Our study provided novel promising protein targets for further mechanistic and therapeutic studies of obesity.

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来源期刊

Human Genetics 生物-遗传学

CiteScore

10.80

自引率

3.80%

发文量

审稿时长

1 months

期刊介绍： Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.