Genetic mapping of etiologic brain cell types for obesity

Timshel, Pascal; Thompson, Jonatan J; Pers, Tune H.

doi:10.7554/elife.55851

Cited by 102 publications

(126 citation statements)

References 114 publications

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“…For both AFS and AFB, all SNPs with p <1×10 -5 in the pooled GWAS meta-analysis were used as input. Based on the results of the tissue enrichment analysis, we used CELLECT 88 to identify nervous system cell types that are enriched for expression of genes in loci reaching p <1×10 -5 in the GWAS, using RNAseq data from mouse brain. 29 A similar approach using tabula muris RNAseq data 87 helped prioritize additional central nervous system and pancreatic cell types for AFS.…”

Section: Methodsmentioning

confidence: 99%

Identification of 370 genetic loci for age at first sex and birth linked to externalising behaviour

Mills

Tropf

Brazel

et al. 2020

Preprint

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1 behaviour, highlighting common aetiology with reproductive 2 biology, externalizing behaviour and longevity 3 4Abstract. The timing of reproductive behaviour -age at first sexual intercourse (AFS) and age at first 31 birth (AFB) -has implications for reproductive health, adolescent development and evolutionary 32 fitness. In the largest genome-wide association study to date (AFS, N=387,338; AFB, N=542,901), we 33 identify 370 independent signals, 11 which are sex-specific, with a 5-6% polygenic score prediction. 34Heritability shifted from 10% for those born in 1940 to 23% for the 1965 birth cohort. Using Genomic 35 SEM, we show that signals are largely driven by the genetics of reproductive biology and 36 externalizing behaviour. This is supported by extensive biological follow-up that isolates key genes 37 related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility (endometriosis, 38 spontaneous abortion) and spermatid differentiation, morphogenesis and binding (KLF17, ZPBP). 39Later AFB is protective against later-life disease (type 2 diabetes, cardiovascular) and associated with 40 longevity. Those from higher childhood socioeconomic circumstances and polygenic scores in the 41 highest deciles (90%+) experience markedly later reproductive onset. Results are relevant for 42 interventions in teenage sexual, reproductive and mental health, deepen our understanding of the 43 drivers of later-life health and longevity, and fuel infertility and functional follow-up experiments. 44 45The timing of onset of human reproductive behaviour -age at first sexual intercourse (AFS) 46 and age at first birth (AFB) -has implications for reproductive health, adolescent 47 528

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Section: Methodsmentioning

confidence: 99%

Identification of 370 genetic loci for age at first sex and birth linked to externalising behaviour

Mills

Tropf

Brazel

et al. 2020

Preprint

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“…Additional insight could be obtained by performing cell prioritization analyses from human post-mortem brain samples and/or induced pluripotent stem cells from individuals with relevant genetic backgrounds using LDSC, MAGMA and DEPICT to identify genes that are predicted to be functionally similar to causal genes. Additionally, the recently developed computational toolkit CELLECT can provide additional insight in cell type enrichment 34 . CELLECT builds upon gene prioritization models, such as LDSC, DEPICT and MAGMA and subsequently performs cell type prioritization analyses using a continuous representation of cell type expression, rather than binary representation.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analyses of RNA-seq and genome-wide data point to enrichment of neuronal cell type subsets in neuropsychiatric disorders

Olislagers

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Adan

et al. 2021

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Neurologic, psychiatric and substance use disorders share a range of symptoms, which could be the result of shared genetic background. Many genetic loci have been identified for these disorders using genome-wide association studies, but conclusive evidence about cell types wherein these loci are active is lacking. We aimed to uncover implicated brain cell types in neuropsychiatric traits and to assess consistency in results across RNA datasets and methods. We therefore comprehensively employed cell-type enrichment methods by integrating single-cell transcriptomic data from mouse brain regions with an unprecedented dataset of 42 human genome-wide association study results of neuropsychiatric, substance use and behavioral brain-related traits (n=12,544,007). Single-cell transcriptomic datasets from the Karolinska Institute and the 10x Genomics dataset were used. Cell type enrichment was determined using Linkage Disequilibrium Score Regression, Multi-marker Analysis of GenoMic Annotation, and Data-driven Expression Prioritized Integration for Complex Traits. We found the largest degree of consistency across methods for implication of pyramidal cells in schizophrenia and cognitive performance. For other phenotypes, such as bipolar disorder, two methods implicated the same cell types, i.e. medium spiny neurons and pyramidal cells. For autism spectrum disorders and anorexia nervosa, no consistency in implicated cell types was observed across methods. We found no evidence for astrocytes being consistently implicated in neuropsychiatric traits. In conclusion, we provide comprehensive evidence for a subset of neuronal cell types being consistently implicated in several, but not all psychiatric disorders, while non-neuronal cell types seem less implicated.

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“…Hierarchical clustering and marker gene analysis for our 24 mouse VMH neuron clusters using CELLEX (Timshel, Thompson, and Pers 2020) revealed that many cell groups were highly related to other VMH neuron clusters (Fig. 2D, E; Table 3).…”

Section: A Simplified Parceling Scheme Defines Anatomically-distinct Vmh Neuron Populationsmentioning

confidence: 98%

Cross-Species Analysis Defines the Conservation of Anatomically-Segregated VMH Neuron Populations

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Sabatini

True

et al. 2021

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The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing Translating Ribosome Affinity Purification with RNA sequencing (TRAP-seq) data with snRNA-seq data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of 6 major genetically- and anatomically-differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously-suggested unique roles for leptin receptor (Lepr)-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.

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Genetic mapping of etiologic brain cell types for obesity

Cited by 102 publications

References 114 publications

Identification of 370 genetic loci for age at first sex and birth linked to externalising behaviour

Identification of 370 genetic loci for age at first sex and birth linked to externalising behaviour

Comprehensive analyses of RNA-seq and genome-wide data point to enrichment of neuronal cell type subsets in neuropsychiatric disorders

Cross-Species Analysis Defines the Conservation of Anatomically-Segregated VMH Neuron Populations

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