ABSTRACT: The hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions. However, our understanding of the underlying cellular components and neurocircuitries have, until recently, emerged primarily from rodent studies. Here, we combine single-nucleus sequencing of 433,369 human hypothalamic cells with spatial transcriptomics, generating a comprehensive spatio-cellular transcriptional map of the hypothalamus, the ‘HYPOMAP’. Whilst conservation of neuronal cell types between humans and mice, based on transcriptomic identity, is generally high, there are notable exceptions. Specifically, there are significant disparities in the identity of POMC neurons and in the expression levels of GPCRs between the two species that carry direct implications for currently approved obesity treatments. Out of the 452 hypothalamic cell types, we find 291 neuronal clusters are significantly enriched for expression of BMI GWAS genes. This enrichment is driven by 426 ‘effector’ genes. Rare deleterious variants in 6 of these, MC4R, PCSK1, POMC, CALCR, BSN and CORO1A, associate with BMI at population level, and CORO1A has not previously been linked to BMI. Thus, HYPOMAP provides a detailed atlas of the human hypothalamus in a spatial context and serves as an important resource to identify novel druggable targets for treating a wide range of conditions, including reproductive, circadian, and metabolic disorders.
