CAS Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
J Diabetes Investig. 2024 Jan;15(1):52-62. doi: 10.1111/jdi.14125. Epub 2023 Dec 29.
Nearly 85% of maternally inherited diabetes and deafness (MIDD) are caused by the m.3243A>G mutation in the mitochondrial DNA. However, the clinical phenotypes of MIDD may also be influenced by the nuclear genome, this study aimed to investigate nuclear genome variants that influence clinical phenotypes associated with m.3243A>G mutation in MIDD based on whole-genome sequencing of the patients belonging to pedigrees.
We analyzed a whole-genome sequencing (WGS) dataset from blood samples of 38 MIDD patients with the m.3243A > G mutation belonging to 10 pedigrees, by developing a Kinship-graph convolutional network approach, called Ki-GCN, integrated with the conventional genome-wide association study (GWAS) methods.
We identified eight protective alleles in the nuclear genome that have protective effects against the onset of MIDD, related deafness, and also type 2 diabetes. Based on these eight protective alleles, we constructed an effective logistic regression model to predict the early or late onset of MIDD patients.
There are protective alleles in the nuclear genome that are associated with the onset-age of MIDD patients and might also provide protective effects on the deafness derived from MIDD patients.
约 85% 的母系遗传糖尿病和耳聋（MIDD）是由线粒体 DNA 中的 m.3243A>G 突变引起的。然而，MIDD 的临床表型也可能受到核基因组的影响，本研究旨在通过对属于家系的患者的全基因组测序，研究影响与 m.3243A>G 突变相关的临床表型的核基因组变异。
我们通过开发一种称为 Ki-GCN 的亲缘关系图卷积网络方法，结合传统的全基因组关联研究（GWAS）方法，对来自 10 个家系的 38 名携带 m.3243A>G 突变的 MIDD 患者的全基因组测序（WGS）数据集进行了分析。
我们在核基因组中鉴定出了八个保护性等位基因，这些等位基因对 MIDD、相关耳聋和 2 型糖尿病的发病有保护作用。基于这八个保护性等位基因，我们构建了一个有效的逻辑回归模型，以预测 MIDD 患者的早发或晚发。
核基因组中存在与 MIDD 患者发病年龄相关的保护性等位基因，这些基因可能对 MIDD 患者的耳聋也有保护作用。
