翁凯
(2022-06-30 22:15):
#paper 10.1038/s41588-018-0129-5。Nature Genetics。2018。Genetic identification of brain cell types underlying schizophrenia。貌似是第一批利用单细胞转录组来定位遗传学研究积累的候选致病基因富集在哪些细胞类型。这有利于进行更细致的机制研究。
IF:31.700Q1
Nature genetics,
2018-06.
DOI: 10.1038/s41588-018-0129-5
PMID: 29785013
PMCID:PMC6477180
Genetic identification of brain cell types underlying schizophrenia
翻译
精神分裂症脑细胞类型的基因鉴定
Abstract:
With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia.
翻译
除了少数例外,关于精神分裂症遗传基础的知识的显着进展并没有集中在可以自信地用于精确实验建模的发现上。通过应用来自单细胞RNA测序的大脑细胞分类学知识,我们评估了与精神分裂症有关的基因组位点是否映射到特定的脑细胞类型。我们发现,常见变异的基因组结果一致地映射到锥体细胞、中棘神经元(MSN)和某些中间神经元,但对胚胎细胞、祖细胞或神经胶质细胞的一致性要低得多。这些富集是由于在这些细胞类型中的每一种中特异性表达的基因集造成的。我们还发现,许多以前与精神分裂症相关的不同基因集(参与突触功能的基因,编码与FMRP相互作用的mRNA,抗精神病靶点等)通常与相同的脑细胞类型有关。我们的研究结果提出了一个简洁的解释:精神分裂症的常见变异遗传结果指向有限的神经元集,而基因集指向相同的细胞。与MSNs相关的遗传风险与谷氨酸能锥体细胞和中间神经元的遗传风险没有重叠,这表明不同的细胞类型在精神分裂症中具有生物学上不同的作用。