Human HYPOMAP: A comprehensive spatio-cellular map of the human hypothalamus

Abstract

AbstractThe hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions. However, our understanding of the underlying cellular components and circuitry, have, until recently, emerged primarily from rodent studies. Here, we combine a single-nucleus sequencing database of 433,369 human hypothalamic cells, with spatial transcriptomics, to present a comprehensive spatio-cellular transcriptional map of the human hypothalamus, the ‘HYPOMAP’. Analysing hypothalamic leptin melanocortin pathway neuronal populations that play a role in appetite control, we identify spatially distinct populations of arcuate nucleusPOMCandAGRPneurons, and their receptorsMC3RandMC4R. Next, we map the cells expressing incretin receptors, targets of the new generation of anti-obesity medications, and uncover transcriptionally distinctGLP1RandGIPR-expressing cellular populations. Finally, out of the 458 hypothalamic cell types in HYPOMAP, we find 182 neuronal clusters are significantly enriched in expression of BMI GWAS genes. This enrichment is driven by 375 ‘effector’ genes, with rare deleterious variants in 6 of these;MC4R,PCSK1,POMC,CALCR,BSNandCORO1A, the last of which has previously not been linked to obesity; being significantly associated with changes in BMI at the population level. Thus, the 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.