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<1.6×10−4). Using genes harboring coding mutations associated with obesity, we replicated midbrain cell types from the anterior pretectal nucleus and periaqueductal gray (p<1.2×10−4). 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.

中文翻译：

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肥胖病因脑细胞类型的遗传定位

介导肥胖倾向的潜在细胞类型在很大程度上仍不清楚。在这里，我们整合了最近发表的来自 727 种外周和神经系统细胞类型的单细胞 RNA 测序 (scRNA-seq) 数据，这些细胞类型跨越 17 个小鼠器官，以及来自 >457,000 个人的体重指数 (BMI) 全基因组关联研究 (GWAS) 数据. 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、丘脑、皮层、脑桥、髓质、苍白球中鉴定了 26 种专门的神经元细胞类型，这些细胞类型的 BMI 遗传性显着丰富。 p<1.6×10-4）。使用含有与肥胖相关的编码突变的基因，我们从前顶盖前核和导水管周围灰质中复制了中脑细胞类型（p<1.2×10-4）。一起，