In general, the far majority of trait-associated SNPs are located in regulatory regions and hence, unlike coding variants, tagging genetic intervals (or loci) rather than implicating specific genes. In recent years, genome-wide association studies (GWAS) have identified about a thousand common (minor allele frequency, MAF ≥0.1) single-nucleotide polymorphisms (SNPs) that associate with body mass index (BMI, defined as weight in kilogram divided by height in meters squared), a heritable and commonly used proxy phenotype for obesity ( Locke et al., 2015 Yengo et al., 2018).
However, despite an increasing number of genes, cell types and neuronal circuits being implicated in murine energy homeostasis, the identity of brain cell types that drive susceptibility to human obesity remains largely unknown and a systematic assessment of cell types’ relevance in obesity is currently lacking. the sight or smell of food) that act in concert to regulate feeding behavior and energy stores ( Grill, 2006 Zeltser, 2018 Grill and Hayes, 2012). viscerosensory input from the gastrointestinal tract) or external stimuli (e.g. Yet growing evidence suggests that susceptibility to obesity is distributed across numerous brain areas that receive signals emanating from internal sources (e.g. Studies of monogenic obesity syndromes and rodent models of obesity have identified melanocortin signaling circuits in the mediobasal and paraventricular hypothalamus as key components in energy homeostasis and obesity ( Morton et al., 2014 Farooqi and O'Rahilly, 2006 Betley et al., 2013). Identification of genes and cell types underlying susceptibility to human obesity remains a critically important step toward a better understanding of mechanisms causing the disease ( Hekselman and Yeger-Lotem, 2020). 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. 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). 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). 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. The underlying cell types mediating predisposition to obesity remain largely obscure.
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