Nandi Sutanu, Zhu Yuehua, Gillenwater Lucas A, Subirana-Granés Marc, Zhang Haoyu, Janani Negar, Greene Casey, Pividori Milton, Chikina Maria, Costello James C
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA, School of Medicine, Tsinghua University, Beijing, China.
Pac Symp Biocomput. 2025;30:412-425. doi: 10.1142/9789819807024_0030.
Down syndrome (DS), caused by the triplication of chromosome 21 (T21), is a prevalent genetic disorder with a higher incidence of obesity. Traditional approaches have struggled to differentiate T21-specific molecular dysregulation from general obesity-related processes. This study introduces the omni-PLIER framework, combining the Pathway-Level Information ExtractoR (PLIER) with the omnigenic model, to uncover molecular mechanisms underlying obesity in DS. The PLIER framework aligns gene expression data with biological pathways, facilitating the identification of relevant molecular patterns. Using RNA sequencing data from the Human Trisome Project, omni-PLIER identified latent variables (LVs) significantly associated with both T21 and body mass index (BMI). Elastic net regression and causal mediation analysis revealed LVs mediating the effect of karyotype on BMI. Notably, LVs involving glutathione peroxidase-1 (GPX1) and MCL1 apoptosis regulator, BCL2 family members emerged as crucial mediators. These findings provide insights into the molecular interplay between DS and obesity. The omni-PLIER model offers a robust methodological advancement for dissecting complex genetic disorders, with implications for understanding obesity-related processes in both DS and the general population.
唐氏综合征（DS）由21号染色体三体性（T21）引起，是一种常见的遗传性疾病，肥胖发生率较高。传统方法一直难以区分T21特异性分子失调与一般肥胖相关过程。本研究引入了全基因组多基因风险评分（omni-PLIER）框架，将通路水平信息提取器（PLIER）与全基因模型相结合，以揭示DS中肥胖的分子机制。PLIER框架将基因表达数据与生物通路对齐，有助于识别相关分子模式。利用来自人类三体项目的RNA测序数据，omni-PLIER识别出与T21和体重指数（BMI）均显著相关的潜在变量（LVs）。弹性网络回归和因果中介分析表明，LVs介导了核型对BMI的影响。值得注意的是，涉及谷胱甘肽过氧化物酶-1（GPX1）和MCL1凋亡调节因子、BCL2家族成员的LVs成为关键介质。这些发现为DS与肥胖之间的分子相互作用提供了见解。omni-PLIER模型为剖析复杂遗传疾病提供了强大的方法学进展，对理解DS和普通人群中与肥胖相关的过程具有重要意义。
