Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Elife. 2020 Sep 21;9:e55851. doi: 10.7554/eLife.55851.
The underlying cell types mediating predisposition to obesity remain largely obscure. Here, we integrated recently published single-cell RNA-sequencing (scRNA-seq) data from 727 peripheral and nervous system cell types spanning 17 mouse organs with body mass index (BMI) genome-wide association study (GWAS) data from >457,000 individuals. Developing a novel strategy for integrating scRNA-seq data with GWAS data, we identified 26, exclusively neuronal, cell types from the hypothalamus, subthalamus, midbrain, hippocampus, thalamus, cortex, pons, medulla, pallidum that were significantly enriched for BMI heritability (p<1.6×10). Using genes harboring coding mutations associated with obesity, we replicated midbrain cell types from the anterior pretectal nucleus and periaqueductal gray (p<1.2×10). Together, our results suggest that brain nuclei regulating integration of sensory stimuli, learning and memory are likely to play a key role in obesity and provide testable hypotheses for mechanistic follow-up studies.
介导肥胖易感性的潜在细胞类型在很大程度上仍不清楚。在这里，我们整合了来自 727 种外周和神经系统细胞类型的最新发表的单细胞 RNA 测序 (scRNA-seq) 数据，这些细胞类型跨越了 17 种小鼠器官，以及来自 >457000 个人的体重指数 (BMI) 全基因组关联研究 (GWAS) 数据。通过开发一种将 scRNA-seq 数据与 GWAS 数据整合的新策略，我们从下丘脑、下丘脑、中脑、海马体、丘脑、皮质、脑桥、延髓、苍白球中鉴定出 26 种仅存在于神经元中的细胞类型，这些细胞类型在 BMI 遗传率方面显著富集（p<1.6×10）。利用与肥胖相关的编码突变基因，我们复制了前脑桥核和导水管周围灰质中的中脑细胞类型（p<1.2×10）。总之，我们的研究结果表明，调节感觉刺激整合、学习和记忆的大脑核可能在肥胖中发挥关键作用，并为机制后续研究提供了可测试的假说。
