【Nature Genetics】2023年11月-2024年3月刊论文导读
期刊介绍：
Nature Genetics创刊于1992年，由Nature Research出版商出版，发表最高质量的遗传学研究。它包括对人类和植物性状以及其他生物模式的遗传和功能基因组研究。目前，该期刊聚焦于通过扰动实验研究常见和复杂疾病的遗传基础以及基因网络的功能机制、结构和进化。在学术领域中，它享有极高的学术影响力，属于国际顶尖期刊之一，其影响因子高达41.307。
Volume 55 Issue 12, December 2023
1.Phenotype integration improves power and preserves specificity in biobank-based genetic studies of major depressive disorder
Volume 56 Issue 2, February 2024
13.Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank
英国生物样本库中胰岛素抵抗标志物TG：HDL-C的综合遗传研究
表型整合改善了基于Biobank的重度抑郁症遗传研究的效力并保留了特异性
美国芝加哥大学遗传部，加州大学计算机科学系
Abstract：
Biobanks often contain several phenotypes relevant to diseases such as major depressive disorder (MDD), with partly distinct genetic architectures. Researchers face complex tradeoffs between shallow (large sample size, low specificity/sensitivity) and deep (small sample size, high specificity/sensitivity) phenotypes, and the optimal choices are often unclear. Here we propose to integrate these phenotypes to combine the benefits of each. We use phenotype imputation to integrate information across hundreds of MDD-relevant phenotypes, which significantly increases genome-wide association study (GWAS) power and polygenic risk score (PRS) prediction accuracy of the deepest available MDD phenotype in UK Biobank, LifetimeMDD. We demonstrate that imputation preserves specificity in its genetic architecture using a novel PRS-based pleiotropy metric. We further find that integration via summary statistics also enhances GWAS power and PRS predictions, but can introduce nonspecific genetic effects depending on input. Our work provides a simple and scalable approach to improve genetic studies in large biobanks by integrating shallow and deep phenotypes.
中文摘要：
UK Biobank中通常包含多种与疾病相关的表型，例如重度抑郁症（MDD），其具有部分不同的遗传结构。研究人员在浅层（样本量大，特异性/敏感性低）和深层（样本量小，特异性/敏感性高）表型之间面临着复杂的权衡取舍，而最佳选择往往并不明确。在此，本研究提出整合这些表型，以结合每种表型各自的优势。使用表型插补法整合数百种与MDD相关的表型信息，这显著提高了UK Biobank中最深可用的LifetimeMDD表型的全基因组关联研究（GWAS）效力和多基因风险评分（PRS）的预测准确性。研究证明，使用一种新的基于PRS的多效性度量，插补法保留了其遗传结构中的特异性。研究进一步发现，通过汇总统计进行整合也可以增强GWAS的效力和PRS的预测性，但可能会根据输入而引入非特异性遗传效应。该研究提供了一种简单且可扩展的方法，通过整合浅层和深层表型来改进大型生物库中的遗传学研究。
2.Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications
大麻使用障碍的多种族全基因组关联研究对疾病生物学和公共卫生学产生影响
美国纽黑文耶鲁大学医学院
Abstract：
As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (ncases = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking.
中文摘要：
随着大麻的娱乐性使用在许多地方被合法化，且其医疗用途也得到广泛批准，人们越来越担心大麻使用障碍（CanUD）的问题，该障碍与多种医学并发症相关。本研究在“百万退伍军人计划”（MVP）中进行了CanUD的全基因组关联研究，随后在来自四个广泛种族的1,054,365名个体（n cases=64, 314）中进行荟萃分析（欧洲n=886,025，非洲n=123,208，混血美国人n=38,289，东亚n=6,843）。应用群体特异方法来计算每个种族内的基于单核苷酸多态性（SNP）的遗传力。除了人数最少的东亚种族外，在其他群体中均观察到具有统计学意义的基于SNP的CanUD遗传力。研究发现了每个种族特有的全基因组显著位点：欧洲人22个，非洲人和东亚人各2个，混血美国人1个。基于遗传信息的因果关系分析表明，CanUD的遗传易感性可能对肺癌风险产生影响，这表明未来可能出现意想不到的医疗和精神公共卫生后果，需要进一步研究将CanUD对肺癌的风险与其他已知风险因素（如吸烟）分开。
3.A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains
人类和小鼠大脑中衰老和阿尔茨海默病发病相关的细胞群动态变化和分子特征概览
美国洛克菲勒大学单细胞基因组学和种群动力学实验室
Abstract：
Conventional methods fall short in unraveling the dynamics of rare cell types related to aging and diseases. Here we introduce EasySci, an advanced single-cell combinatorial indexing strategy for exploring age-dependent cellular dynamics in the mammalian brain. Profiling approximately 1.5 million single-cell transcriptomes and 400,000 chromatin accessibility profiles across diverse mouse brains, we identified over 300 cell subtypes, uncovering their molecular characteristics and spatial locations. This comprehensive view elucidates rare cell types expanded or depleted upon aging. We also investigated cell-type-specific responses to genetic alterations linked to Alzheimer’s disease, identifying associated rare cell types. Additionally, by profiling 118,240 human brain single-cell transcriptomes, we discerned cell- and region-specific transcriptomic changes tied to Alzheimer’s pathogenesis. In conclusion, this research offers a valuable resource for probing cell-type-specific dynamics in both normal and pathological aging.
中文摘要：
传统方法在揭示与衰老和疾病相关的罕见细胞类型的动态方面存在不足。本研究介绍EasySci，一种先进的单细胞组合索引策略，用于探索哺乳动物大脑中年龄相关的细胞动力学。通过分析不同的小鼠大脑中大约150万个单细胞转录组和40万个染色质可及性图谱，本研究鉴定了300多种细胞亚型，揭示了它们的分子特征和空间位置。这一概览阐明了在衰老时扩增或耗竭的罕见细胞类型。进一步研究细胞类型对阿尔茨海默病相关的遗传改变的特异性反应，确定了相关的罕见细胞类型。此外，通过分析118，240个人脑单细胞转录组，发现与阿尔茨海默病发病机制相关的细胞和区域特异性转录组变化。总之，这项研究为探索正常和病理衰老中的细胞类型特异性动力学提供了宝贵的资源。
4.Isoform-level transcriptome-wide association uncovers genetic risk mechanisms for neuropsychiatric disorders in the human brain
同种异构体水平的转录组广泛关联揭示人脑神经精神疾病的遗传风险机制
美国宾夕法尼亚大学、美国德克萨斯大学MD安德森癌症中心
Abstract：
Methods integrating genetics with transcriptomic reference panels prioritize risk genes and mechanisms at only a fraction of trait-associated genetic loci, due in part to an overreliance on total gene expression as a molecular outcome measure. This challenge is particularly relevant for the brain, in which extensive splicing generates multiple distinct transcript-isoforms per gene. Due to complex correlation structures, isoform-level modeling from cis-window variants requires methodological innovation. Here we introduce isoTWAS, a multivariate, stepwise framework integrating genetics, isoform-level expression and phenotypic associations. Compared to gene-level methods, isoTWAS improves both isoform and gene expression prediction, yielding more testable genes, and increased power for discovery of trait associations within genome-wide association study loci across 15 neuropsychiatric traits. We illustrate multiple isoTWAS associations undetectable at the gene-level, prioritizing isoforms of AKT3, CUL3 and HSPD1 in schizophrenia and PCLO with multiple disorders. Results highlight the importance of incorporating isoform-level resolution within integrative approaches to increase discovery of trait associations, especially for brain-relevant traits.
中文摘要：
将遗传学与转录组学相结合的方法研究风险基因和机制仅在一小部分性状相关遗传位点中优先考虑，部分原因是过度依赖总基因表达作为分子结果测量。这一挑战与大脑特别相关，在大脑中，广泛的剪接为每个基因产生多种不同的转录异构体。由于复杂的相关性结构，顺式窗口变体的异构体水平建模需要方法创新。在这里，本研究介绍了isoTWAS工具，这是一个整合遗传学、同种型水平表达和表型关联的多变量逐步框架。与基因水平的方法相比，isoTWAS改进了异构体和基因表达预测，产生了更多可测试的基因，并提高了在15个神经精神特征的全基因组关联研究位点内发现特征关联的能力。本研究阐明了在基因水平上无法检测到的多种isoTWAS关联，在患有多种疾病的精神分裂症和PCLO中优先考虑AKT3、CUL3和HSPD1的亚型。总之，这一研究结果强调了在综合方法中结合异构体水平分辨率的重要性，以增加特征关联的发现，特别是对于大脑相关性状。
5.East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease
东亚特异性和跨种族全基因组荟萃分析为消化性溃疡疾病提供了机制见解
东京大学前沿科学研究生院复杂性状基因组学实验室
Abstract：
Peptic ulcer disease (PUD) refers to acid-induced injury of the digestive tract, occurring mainly in the stomach (gastric ulcer (GU)) or duodenum (duodenal ulcer (DU)). In the present study, we conducted a large-scale, cross-ancestry meta-analysis of PUD combining genome-wide association studies with Japanese and European studies (52,032 cases and 905,344 controls), and discovered 25 new loci highly concordant across ancestries. An examination of GU and DU genetic architecture demonstrated that GUs shared the same risk loci as DUs, although with smaller genetic effect sizes and higher polygenicity than DUs, indicating higher heterogeneity of GUs. Helicobacter pylori (HP)-stratified analysis found an HP-related host genetic locus. Integrative analyses using bulk and single-cell transcriptome profiles highlighted the genetic factors of PUD being enriched in the highly expressed genes in stomach tissues, especially in somatostatin-producing D cells. Our results provide genetic evidence that gastrointestinal cell differentiations and hormone regulations are critical in PUD etiology.
中文摘要：
消化性溃疡病（PUD）是指消化道受胃酸损伤的疾病，主要发生在胃（胃溃疡，GU）或十二指肠（十二指肠溃疡，DU）。本研究进行了一项大规模、跨种族的PUD荟萃分析，将全基因组关联研究与日本和欧洲的研究（52，032例和905，344例对照）相结合，发现了25个跨种族高度一致的新位点。对GU和DU的遗传结构进行检查发现，尽管GU的遗传效应较小且多基因性较高，但GU和DU共享相同的风险位点，这表明GU的异质性更高。幽门螺杆菌（HP）分层分析发现了一个与HP相关的宿主遗传位点。使用整体和单细胞转录组谱进行的综合分析强调了PUD的遗传因素在胃组织中高表达基因中的富集，特别是在产生生长抑素的D细胞中。我们的结果为胃肠道细胞分化和激素调节在PUD发病机制中的关键作用提供了遗传证据。
6.Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression
非编码突变导致超级增强子重定位，使B淋巴瘤进展期间蛋白质合成失调
中国香港科技大学
Abstract：
Whole-genome sequencing of longitudinal tumor pairs representing transformation of follicular lymphoma to high-grade B cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma) identified coding and noncoding genomic alterations acquired during lymphoma progression. Many of these transformation-associated alterations recurrently and focally occur at topologically associating domain resident regulatory DNA elements, including H3K4me3 promoter marks located within H3K27ac super-enhancer clusters in B cell non-Hodgkin lymphoma. One region found to undergo recurrent alteration upon transformation overlaps a super-enhancer affecting the expression of the PAX5/ZCCHC7 gene pair. ZCCHC7 encodes a subunit of the Trf4/5-Air1/2-Mtr4 polyadenylation-like complex and demonstrated copy number gain, chromosomal translocation and enhancer retargeting-mediated transcriptional upregulation upon lymphoma transformation. Consequently, lymphoma cells demonstrate nucleolar dysregulation via altered noncoding 5.8S ribosomal RNA processing. We find that a noncoding mutation acquired during lymphoma progression affects noncoding rRNA processing, thereby rewiring protein synthesis leading to oncogenic changes in the lymphoma proteome.
中文摘要：
对滤泡性淋巴瘤和其转化的具有MYC和BCL2重排的高级别B细胞淋巴瘤进行配对的全基因组测序，确定了淋巴瘤进展过程中获得的编码和非编码基因组改变。其中许多与转化相关的改变反复且局部地发生在拓扑关联域常驻调控DNA元件上，包括位于B细胞非霍奇金淋巴瘤中H3K27ac超级增强子簇内的H3K4me3启动子标记。本研究发现一个在转化过程中发生反复改变的区域与影响PAX5/ZCCHC7基因对表达的超级增强子重叠。ZCCHC7编码Trf4/5-Air1/2-Mtr4多聚腺苷酸化样复合体的一个亚基，并在淋巴瘤转化过程中表现出拷贝数增加、染色体易位和增强子重定向介导的转录上调。因此，淋巴瘤细胞通过改变非编码5.8S核糖体RNA的加工过程而表现出核仁失调。我们发现，淋巴瘤进展过程中获得的非编码突变影响了非编码rRNA的加工，从而重塑了蛋白质合成，导致淋巴瘤蛋白质组中的致癌变化。
7.Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance
宫颈鳞状细胞癌的多组学分析确定了具有生物学和临床相关性的细胞生态系统
华中科技大学
Abstract：
Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments. Bidirectional interactions between epithelial-cytokeratin malignant cells and immunosuppressive cancer-associated fibroblasts form an immune exclusionary microenvironment through transforming growth factor β pathway signaling mediated by FABP5. In Epi-Imm tumors, malignant cells interact with natural killer and T cells through interferon signaling. Preliminary analysis of samples from a cervical cancer clinical trial (NCT04516616) demonstrated neoadjuvant chemotherapy induces a state transition to Epi-Imm, which correlates with pathological complete remission following treatment with immune-checkpoint blockade. These findings deepen the understanding of cellular state diversity in CSCC.
中文摘要：
宫颈鳞癌（CSCC）对免疫检查点阻断疗法的反应有限。本研究进行了多组学分析，包括单细胞RNA测序、空间转录组学和空间蛋白质组学，结合遗传和药理学，系统性揭示了CSCC的瘤内异质性图谱。三种肿瘤状态（上皮细胞角蛋白、上皮免疫（Epi-imm）和上皮衰老）概括了鳞状分化的不同阶段，显示出不同的肿瘤免疫微环境。上皮细胞角蛋白恶性细胞与免疫抑制性癌症相关成纤维细胞之间的双向相互作用通过转化FABP5介导的生长因子β通路信号转导形成免疫排他性微环境。在Epi-Imm肿瘤中，恶性细胞通过干扰素信号转导与自然杀伤细胞和T细胞相互作用。对宫颈癌临床试验（NCT04516616）样本的初步分析表明，新辅助化疗可诱导肿瘤向Epi-Imm 的状态转换，这与免疫检查点阻断治疗后的病理完全缓解相关。这些发现加深了对CSCC细胞状态多样性的理解。
8.Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens
通过正交CRISPR筛选鉴定的人CD8+ T细胞功能的转录和表观遗传调节因子
杜克大学生物医学工程系
Abstract：
Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8+ T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.
中文摘要：
采用过继性T细胞疗法的临床反应与细胞产物的转录和表观遗传状态有关。因此，发现T细胞基因网络的调控因子及其相应的表型，有可能改善T细胞疗法。本研究开发了一种集合的表观遗传CRISPR筛选方法，以系统地分析激活或抑制120个转录和表观遗传调控因子对人类CD8+ T细胞状态的影响。本研究发现BATF3过表达促进了记忆T细胞的特定特征，并减弱了与细胞毒性、调节性T细胞功能和耗竭相关的基因程序。在慢性抗原刺激下，BATF3过表达可逆转T细胞耗竭的表型和表观遗传特征。此外，BATF3在体外和体内肿瘤模型中增强了CAR T细胞的效力，并编程了一个与过继性T细胞疗法的积极临床反应相关的转录谱。最后，本研究进行CRISPR敲除筛选，确定了BATF3基因网络的辅因子和下游介质。
Volume 56 Issue 1, January 2024
9.Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease
帕金森病的多祖先全基因组关联meta分析
Abstract：
Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations.
中文摘要：
尽管使用全基因组关联研究已经确定了90多个帕金森病的独立风险变异，但大多数研究一次仅在一个人群中进行。本研究对帕金森病进行了大规模的多族群荟萃分析，其中包括49,049例病例、18,785例proxy病例和2,458,063例对照，包括欧洲、东亚、拉丁美洲和非洲血统的个体。荟萃分析确定了78个独立的全基因组显著位点，包括12个潜在的新位点（MTF2、PIK3CA、ADD1、SYBU、IRS2、USP8、PIGL、FASN、MYLK2、USP25、EP300和PPP6R2），并在6个已知的位点上精细定位了6个可能的因果变异体。通过将结果与公开可用的eQTL数据相结合，本研究在这些新位点中确定了25个可能的风险基因，其表达与帕金森病风险相关。这项研究旨在为未来识别非欧洲人群中的帕金森病位点的工作奠定基础。
10.The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance
APOBEC3B在肺癌进化和靶向治疗耐药中的作用
美国加州大学旧金山分校
Abstract：
In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.
中文摘要：
本研究评估了载脂蛋白B mRNA编辑催化亚基样（APOBEC）酶APOBEC3B（A3B）对表皮生长因子受体（EGFR）驱动的肺癌影响。在EGFR突变（EGFRmut）非小细胞肺癌（NSCLC）小鼠模型中，A3B的表达抑制了肿瘤的发生，而在EGFR靶向癌症治疗的肿瘤中，A3B的表达与治疗耐药相关。对接受EGFR靶向治疗的人NSCLC模型的分析显示A3B表达上调，并发现治疗诱导的核因子κB（NF-κB）激活是A3B表达的诱导因子。在靶向治疗的人类非小细胞肺癌临床前模型中，在缺乏A3B的情况下观察到存活率显著降低。在接受EGFR靶向治疗的NSCLC患者中证实了A3B的上调。本研究揭示了A3B在非小细胞肺癌中的多方面作用，并确定A3B作为靶向癌症治疗更持久反应的潜在靶点。
11.CellCharter reveals spatial cell niches associated with tissue remodeling and cell plasticity
CellCharter揭示了与组织重塑和细胞可塑性相关的空间细胞生态位
瑞士洛桑大学计算生物系
Abstract：
Tissues are organized in cellular niches, the composition and interactions of which can be investigated using spatial omics technologies. However, systematic analyses of tissue composition are challenged by the scale and diversity of the data. Here we present CellCharter, an algorithmic framework to identify, characterize, and compare cellular niches in spatially resolved datasets. CellCharter outperformed existing approaches and effectively identified cellular niches across datasets generated using different technologies, and comprising hundreds of samples and millions of cells. In multiple human lung cancer cohorts, CellCharter uncovered a cellular niche composed of tumor-associated neutrophil and cancer cells expressing markers of hypoxia and cell migration. This cancer cell state was spatially segregated from more proliferative tumor cell clusters and was associated with tumor-associated neutrophil infiltration and poor prognosis in independent patient cohorts. Overall, CellCharter enables systematic analyses across data types and technologies to decode the link between spatial tissue architectures and cell plasticity.
中文摘要：
组织中按照特定的细胞生态位排列，这些生态位的组成和相互作用可以使用空间组学技术进行研究。然而，对组织成分的系统分析面临着数据规模和多样性的挑战。本研究提出了一个名为CellCharter的算法框架，用于识别、表征和比较空间解析数据集中的细胞生态位。CellCharter在性能上超越了现有方法，并有效地识别了使用不同技术生成的包含数百个样本和数百万个细胞的数据集中的细胞生态位。在多个肺癌患者队列中，CellCharter发现了一种由表达缺氧和细胞迁移标志物的肿瘤相关中性粒细胞和癌细胞组成的细胞生态位。这种癌细胞状态在空间上与增殖性更强的肿瘤细胞群分离，并与独立患者队列中的肿瘤相关中性粒细胞浸润和不良预后相关。总体而言，CellCharter能够对不同数据类型和技术进行系统分析，以解码空间组织结构与细胞可塑性之间的联系。
12.Inferring compound heterozygosity from large-scale exome sequencing data
从大规模外显子组测序数据推断复合物杂合性
美国宾夕法尼亚州费城宾夕法尼亚大学医院神经内科
Abstract：
Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n = 125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed causal compound heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.
中文摘要：
当一个基因的两个拷贝都受到有害遗传变异的影响时，就会引发隐性遗传病。当患者的某个基因携带两个潜在致病性变异时，为了进行准确诊断，需要确定这些变异发生在染色体的不同拷贝上（即反式状态），而非同一拷贝上（即顺式状态）。然而，除了亲子检测外，目前用于确定相位的临床方法有限。本研究开发了一种策略，用于推断基因内部罕见变异对的相位，该方法利用了基因组聚合数据库（v2，n＝125，748个外显子组）中观察到的基因型。该方法在三重数据和患有孟德尔疾病且假定为致病性复合杂合变异的患者中，相位估计的准确度都达到了96%。本研究提供了一个公共资源，用于编码变异的相位估计以及反式罕见变异的每个基因计数，这有助于在隐性遗传病背景下解释罕见共变异体。
Volume 56 Issue 2, February 2024
13.Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank
英国生物样本库中胰岛素抵抗标志物TG：HDL-C的综合遗传研究
美国密歇根大学医学院
Abstract：
Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.
中文摘要：
胰岛素抵抗（IR）是公认的代谢性疾病的危险因素。甘油三酯与高密度脂蛋白胆固醇（TG:HDL-C）的比值是IR的替代标志物。本研究对UK Biobank中402,398名欧洲人的TG：HDL-C比率进行了全基因组关联研究，鉴定出369个独立的SNP，其中114个在其他全基因组IR研究中的假发现率校正P值<0.05，使其成为高可信度的IR相关位点。这114个位点中有72个以前未发现与IR相关。经全表型分析，这114个位点可分为5组，富含胰岛素信号传导、脂肪细胞生理学和蛋白质代谢中的重要候选基因。本研究还使用密歇根基因组计划中的51,550名欧洲个体，从高可信度IR相关位点创建了多基因风险评分，并确定了其与糖尿病、高甘油血症、高血压、非酒精性脂肪性肝病和缺血性心脏病的关联。总的来说，这项研究提供了对IR关键的基因、通路、组织和亚型的见解。
14.Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference
重度抑郁症的多种族全基因组关联研究有助于基因座发现、精细定位、基因优先排序和因果推断
英国伦敦大学学院遗传学研究所
Abstract：
Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.
中文摘要：
目前大多数重度抑郁症（MD）的全基因组关联研究（GWAS）都是在欧洲人中进行的。本研究开展了一项关于重度抑郁症的多种族GWAS研究，在之前报告数据的基础上增加了21个队列的数据，包括88,316例MD病例和902,757例对照。这项分析采用了一系列测量方法来定义MD，包括非洲人种（占有效样本量的36%）、东亚人种（26%）和南亚人种（6%）以及西班牙裔/拉美裔参与者（32%）。多种族GWAS发现了53个显著相关的新位点。针对欧洲人种GWAS分析发现的风险位点，可转移到其他人种群体的比预期的少。精细定位得益于样本的多样性。一项转录组范围的关联分析确定了205个显著相关的新基因。这些研究结果表明，对于MD来说，增加遗传研究中的人种多样性和全球多样性可能对发现核心基因和了解基因位点的可转移性尤为重要。
15.Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder
多基因图谱定义了注意力缺陷多动障碍的临床异质性
丹麦罗斯基勒哥本哈根精神卫生服务中心精神卫生中心生物精神病学研究所
Abstract：
Attention deficit hyperactivity disorder (ADHD) is a complex disorder that manifests variability in long-term outcomes and clinical presentations. The genetic contributions to such heterogeneity are not well understood. Here we show several genetic links to clinical heterogeneity in ADHD in a case-only study of 14,084 diagnosed individuals. First, we identify one genome-wide significant locus by comparing cases with ADHD and autism spectrum disorder (ASD) to cases with ADHD but not ASD. Second, we show that cases with ASD and ADHD, substance use disorder and ADHD, or first diagnosed with ADHD in adulthood have unique polygenic score (PGS) profiles that distinguish them from complementary case subgroups and controls. Finally, a PGS for an ASD diagnosis in ADHD cases predicted cognitive performance in an independent developmental cohort. Our approach uncovered evidence of genetic heterogeneity in ADHD, helping us to understand its etiology and providing a model for studies of other disorders.
中文摘要：
注意力缺陷多动障碍（ADHD）是一种复杂的疾病，其长期结果和临床表现具有异质性。目前对于遗传因素对这种异质性的贡献还知之甚少。本研究对14084名确诊个体的病例进行研究，展示了ADHD临床异质性的几个遗传联系。首先，研究将ADHD与自闭症谱系障碍（ASD）共存的病例与仅患有ADHD的病例进行比较，确定了一个全基因组显著位点。其次，研究发现ASD合并ADHD、物质使用障碍合并ADHD或在成年期首次诊断为ADHD的病例具有独特的多基因评分（PGS）特征，这些特征可将其与互补的病例亚组和对照组区分开来。最后，在ADHD病例中，ASD诊断的PGS预测了独立发育队列中的认知表现。该方法揭示了ADHD中的遗传异质性证据，有助于理解其病因，并为其他疾病的研究提供了模型。
16.Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms
常见血液学性状的遗传多基因效应影响JAK2V617F克隆选择和骨髓增生性肿瘤的发展
剑桥大学威康桑格研究所
Abstract：
Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2V617F, are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2V617F clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2V617F positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2V617F carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study showcases how polygenic backgrounds underlying common hematological traits influence both clonal selection on somatic mutations and the subsequent phenotype of cancer.
中文摘要：
骨髓增殖性肿瘤（MPNs）是一种慢性癌症，其特征是成熟血细胞的过度增生。JAK2V617F等致病性体细胞突变在人群中很常见，但只有少数携带者会发展为MPNs。本研究表明，影响常见血液学特征的遗传多基因位点会影响JAK2V617F克隆的增殖。本研究确定了单核细胞计数和血小板压积的多基因风险评分（PGSs）可作为JAK2V617F阳性的新风险因素。几种血液学特征的PGSs影响了不同MPNs亚型的风险，其中两种血小板特征的低PGSs在JAK2V617F携带者中也显示出保护作用，使这些携带者患原发性血小板增多症的可能性比高PGSs的携带者低两到三倍。研究观察到，在没有体细胞驱动突变的情况下，极端的血液学PGSs可能有助于MPNs的诊断。本研究展示了常见血液学特征的多基因背景如何影响体细胞突变上的克隆选择以及随后的癌症表型。
Volume 57 Issue 3, March 2024
17.Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum
突变型亨廷顿Ⅰ在人纹状体和小脑中的细胞型特异性CAG重复序列扩增及毒性
美国纽约洛克菲勒大学分子生物学实验室
Abstract：
Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington’s disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1. Our data support a model in which CAG expansions are necessary but may not be sufficient for cell death and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity.
中文摘要：
亨廷顿病（HD）的关键特征是大脑区域特异的退行性病变和突变亨廷顿蛋白（mHTT）CAG重复序列的体细胞扩增。然而，CAG重复序列扩增、特定细胞类型的死亡以及与这些过程相关的分子事件之间的关系尚未确定。本研究利用荧光激活细胞核分选（FANS）和深度分子分析技术，以深入了解亨廷顿病和对照组供体的人纹状体和小脑细胞类型的特性。CAG重复序列扩增发生在纹状体中等棘状神经元（MSNs）、胆碱能中间神经元和小脑浦肯野神经元中的mHTT中，以及SCA3供体MSNs中的突变ATXN3中。MSNs中的CAG重复序列扩张与MSH2和MSH3（形成MutSβ）水平的升高相关，它们可以抑制FAN1对CAG滑移的核酸内切酶切除。本研究数据支持一个模型，即CAG重复序列扩增是必要的，但可能不足以导致细胞死亡，并确定了与体细胞CAG重复序列扩增和纹状体毒性相关的转录变化。
18.Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy
涉及肌肉特异性蛋白激酶和巨肌蛋白titin的基因遗传导致骨骼肌肌病
英国约翰沃尔顿肌肉萎缩研究中心
Abstract：
In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.
中文摘要：
在双基因遗传中，两个基因中的致病变异必须一起遗传才能导致疾病。在神经肌肉疾病领域，双基因遗传的例子非常少见。本研究表明，编码X连锁的丝氨酸/精氨酸蛋白激酶3的SRPK3中预测的有害变异，只有与TTN基因中的杂合变异同时存在时，才会导致进行性早发性骨骼肌肌病。在76,702名健康男性个体中，并未观察到预测的有害SRPK3/TTN变异同时存在的情况，而统计建模强烈支持双基因遗传作为最佳拟合模型。此外，双突变斑马鱼（srpk3−/−；ttn.1+/−）复制了肌病表型，并显示肌原纤维组织紊乱。转录组数据表明，斑马鱼中srpk3和ttn.1的相互作用发生在转录后水平。本研究提出，影响蛋白激酶SRPK3和巨肌蛋白titin的有害变化的双基因遗传会导致骨骼肌病，并可能作为其他遗传疾病的模型。
19.Multi-omic profiling of clear cell renal cell carcinoma identifies metabolic reprogramming associated with disease progression
透明细胞肾细胞癌的多组学分析确定了与疾病进展相关的代谢重编程
中国武汉华中科技大学同济医学院同济医院泌尿外科
Abstract：
Clear cell renal cell carcinoma (ccRCC) is a complex disease with remarkable immune and metabolic heterogeneity. Here we perform genomic, transcriptomic, proteomic, metabolomic and spatial transcriptomic and metabolomic analyses on 100 patients with ccRCC from the Tongji Hospital RCC (TJ-RCC) cohort. Our analysis identifies four ccRCC subtypes including De-clear cell differentiated (DCCD)-ccRCC, a subtype with distinctive metabolic features. DCCD cancer cells are characterized by fewer lipid droplets, reduced metabolic activity, enhanced nutrient uptake capability and a high proliferation rate, leading to poor prognosis. Using single-cell and spatial trajectory analysis, we demonstrate that DCCD is a common mode of ccRCC progression. Even among stage I patients, DCCD is associated with worse outcomes and higher recurrence rate, suggesting that it cannot be cured by nephrectomy alone. Our study also suggests a treatment strategy based on subtype-specific immune cell infiltration that could guide the clinical management of ccRCC.
中文摘要：
肾透明细胞癌（ccRCC）是一种复杂的疾病，具有显著的免疫和代谢异质性。本研究对同济医院肾细胞癌（TJ-RCC）队列中的100名ccRCC患者进行了基因组、转录组、蛋白质组、代谢组以及空间转录组和代谢组分析。研究确定了四种ccRCC亚型，包括去透明细胞分化型（DCCD）-ccRCC，这是一种具有独特代谢特征的亚型。DCCD癌细胞的特点是脂质滴少、代谢活性低、营养吸收能力强以及增殖率高，从而导致预后不良。通过单细胞和空间轨迹分析，证明DCCD是ccRCC进展的一种常见模式。即使在I期患者中，DCCD也与较差的预后和较高的复发率相关，这表明仅通过肾切除术无法治愈。研究还提出了一种基于亚型特异性免疫细胞浸润的治疗策略，这可以为ccRCC的临床管理提供指导。
20.Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer
通路水平亚型鉴定了与结直肠癌不良临床结果相关的慢循环生物表型
英国贝尔法斯特女王大学帕特里克·约翰斯顿癌症研究中心
Abstract：
Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers.
中文摘要：
使用基因水平的转录数据进行的分子分层已经识别出具有独特基因型和表型特征的亚型，如结直肠癌（CRC）中的共识分子亚型（CMS）。本研究利用基因本体（GO）和生物激活状态信息来进行初步的分子类别探究，而非使用基因水平的数据。通过这种方式，在CRC中定义三个通路衍生的亚型（PDS）：PDS1肿瘤，富含典型/LGR5+干细胞、高度增殖并良好预后；PDS2肿瘤，富含再生/ANXA1+干细胞，具有增加的基质和免疫肿瘤微环境谱系；PDS3肿瘤，代表以前被忽视的CMS2肿瘤中缓慢循环的肿瘤亚群，干细胞减少且分化谱系增加，特别是肠上皮细胞和肠内分泌细胞，在局部晚期疾病中预后最差。这些PDS3表型特征在多个整体和单细胞数据集中都很明显，并标志着一系列微妙的生物状态，这些状态目前在临床前模型中代表性不足，且无法使用现有的亚型分类器进行识别。
21.Genome-wide ATAC-see screening identifies TFDP1 as a modulator of global chromatin accessibility
全基因组ATAC-see筛选确定TFDP1是全染色质可及性的调节剂
日本冈崎SOKENDAI前沿科研研究生院
Abstract：
Chromatin accessibility is a hallmark of active regulatory regions and is functionally linked to transcriptional networks and cell identity. However, the molecular mechanisms and networks that govern chromatin accessibility have not been thoroughly studied. Here we conducted a genome-wide CRISPR screening combined with an optimized ATAC-see protocol to identify genes that modulate global chromatin accessibility. In addition to known chromatin regulators like CREBBP and EP400, we discovered a number of previously unrecognized proteins that modulate chromatin accessibility, including TFDP1, HNRNPU, EIF3D and THAP11 belonging to diverse biological pathways. ATAC-seq analysis upon their knockouts revealed their distinct and specific effects on chromatin accessibility. Remarkably, we found that TFDP1, a transcription factor, modulates global chromatin accessibility through transcriptional regulation of canonical histones. In addition, our findings highlight the manipulation of chromatin accessibility as an approach to enhance various cell engineering applications, including genome editing and induced pluripotent stem cell reprogramming.
中文摘要：
染色质可及性是活跃调控区域的标志，在功能上与转录网络和细胞身份相关。然而，调控染色质可及性的分子机制和网络尚未得到深入研究。本研究结合优化的ATAC-see方法进行了全基因组CRISPR筛选，以识别调控全局染色质可及性的基因。除了已知的染色质调控因子如CREBBP和EP400外，研究还发现了一些先前未被识别的调控染色质可及性的蛋白质，包括属于不同生物通路的TFDP1、HNRNPU、EIF3D和THAP11。敲除这些基因后进行的ATAC-seq分析揭示了它们对染色质可及性的独特和特异的影响。值得注意的是，研究发现转录因子TFDP1通过对经典组蛋白的转录调控来调节全局染色质可及性。此外，研究强调了调控染色质可及性作为一种增强各种细胞工程应用（包括基因组编辑和诱导多能干细胞重编程）的方法的重要性。
汇报人：张子妍
导师：赵宇
编辑：陈秋蓉
审核：任建君、宋瑶
