Zhao Qi-Gang, Ma Xin-Ling, Xu Qian, Song Zi-Tong, Bu Fan, Li Kuan, Han Bai-Xue, Yan Shan-Shan, Zhang Lei, Luo Yuan, Pei Yu-Fang
Department of Orthopedics, Taicang Affiliated Hospital of Soochow University, 58 Changsheng Rd., Suzhou Taicang City, 215400, Jiangsu Province, PR China.
Department of Epidemiology and Biostatistics, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, 199 Ren-ai Rd., Suzhou City, 215123, Jiangsu Province, PR China.
Hum Genet. 2025 Jan;144(1):31-41. doi: 10.1007/s00439-024-02714-w. Epub 2024 Nov 4.
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.
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.
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.
Our study provided novel promising protein targets for further mechanistic and therapeutic studies of obesity.
全基因组关联研究已经确定了数十个与肥胖相关的基因组位点。然而，这些位点背后的功能基因及其详细的遗传机制主要尚不清楚。在本研究中，我们进行了一项综合研究，通过整合来自全基因组、转录组和蛋白质组关联分析的信息，对可能具有功能的基因进行优先级排序。
我们首先对六种肥胖相关性状进行了蛋白质组全关联分析和转录组全关联分析。然后，我们对蛋白质组和转录组关联分析中确定的共享位点进行了共定位分析。最后，我们用其他血浆/血液参考样本验证了所确定的基因。对突出显示的基因进行了其他组织表达、单细胞和组织特异性以及药物可及性评估。
通过蛋白质组全关联研究、转录组全关联研究和共定位分析，我们确定了4个高可信度基因（脂肪酸合酶、细胞间黏附分子1、程序性细胞死亡6相互作用蛋白和14-3-3蛋白β/α），它们在mRNA和蛋白质水平上都一致地影响肥胖性状的变异。这4个基因使用其他血浆/血液参考样本成功得到验证。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，脂肪酸合酶和细胞间黏附分子1在代谢和免疫相关组织及细胞中显著表达。此外，脂肪酸合酶和细胞间黏附分子1已被开发为药物靶点。
我们的研究为肥胖的进一步机制和治疗研究提供了新的有前景的蛋白质靶点。
