Lagisetty Yashwanth, Bourquard Thomas, Al-Ramahi Ismael, Mangleburg Carl Grant, Mota Samantha, Soleimani Shirin, Shulman Joshua M, Botas Juan, Lee Kwanghyuk, Lichtarge Olivier
Department of Biology and Pharmacology, UTHealth McGovern Medical School, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Genom. 2022 Sep 14;2(9). doi: 10.1016/j.xgen.2022.100162. Epub 2022 Jul 26.
Most disease-gene association methods do not account for gene-gene interactions, even though these play a crucial role in complex, polygenic diseases like Alzheimer's disease (AD). To discover new genes whose interactions may contribute to pathology, we introduce GeneEMBED. This approach compares the functional perturbations induced in gene interaction network neighborhoods by coding variants from disease versus healthy subjects. In two independent AD cohorts of 5,169 exomes and 969 genomes, GeneEMBED identified novel candidates. These genes were differentially expressed in AD brains and modulated neurological phenotypes in mice. Four that were differentially overexpressed and modified neurodegeneration are PLEC, UTRN, TP53, and POLD1. Notably, TP53 and POLD1 are involved in DNA break repair and inhibited by approved drugs. While these data show proof of concept in AD, GeneEMBED is a general approach that should be broadly applicable to identify genes relevant to risk mechanisms and therapy of other complex diseases.
大多数疾病-基因关联方法并未考虑基因-基因相互作用，尽管这些相互作用在诸如阿尔茨海默病（AD）等复杂的多基因疾病中起着至关重要的作用。为了发现其相互作用可能导致病理变化的新基因，我们引入了GeneEMBED。这种方法比较了疾病患者与健康受试者的编码变异在基因相互作用网络邻域中引起的功能扰动。在两个分别包含5169个外显子组和969个基因组的独立AD队列中，GeneEMBED鉴定出了新的候选基因。这些基因在AD大脑中差异表达，并调节小鼠的神经表型。四个差异过表达并改变神经退行性变的基因是PLEC、UTRN、TP53和POLD1。值得注意的是，TP53和POLD1参与DNA断裂修复，并受到已批准药物的抑制。虽然这些数据在AD中证明了概念验证，但GeneEMBED是一种通用方法，应该广泛适用于识别与其他复杂疾病的风险机制和治疗相关的基因。
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