华西耳鼻喉前沿学术速递——文献导读（第58期）
【Nature Genetics】2024年10-11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、植物性状和其他生物的遗传和功能基因组研究。目前的重点是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。Nature Genetics在行业领域中学术影响力很高，属于国际一流期刊，影响因子指数31.7。
Nature Genetics Volume 56 Issue 10, October 2024
在2024年10月，Nature Genetics共发表37篇文章，其中包括Comment 3篇，Research Highlights 4篇，News & Views 3篇，Research Briefings 4篇，Review articles 1篇， Articles 20篇，Technical Reports 2篇。主要内容包括全基因组关联分析、统计精细映射、免疫检查点抑制剂治疗的生物标志物等内容。
1.Population-specific putative causal variants shape quantitative traits
人群特异性潜在因果变异塑造数量性状
日本横滨理化学研究所综合医学科学中心心血管基因组学和信息学实验室、统计与转化遗传学实验室等合作发表
Abstract:
Human genetic variants are associated with many traits through largely unknown mechanisms. Here, combining approximately 260,000 Japanese study participants, a Japanese-specific genotype reference panel and statistical fine-mapping, we identified 4,423 significant loci across 63 quantitative traits, among which 601 were new, and 9,406 putatively causal variants. New associations included Japanese-specific coding, splicing and noncoding variants, exemplified by a damaging missense variant rs730881101 in TNNT2 associated with lower heart function and increased risk for heart failure (P=1.4×10−15 and odds ratio=4.5, 95% confidence interval=3.1–6.5). Putative causal noncoding variants were supported by state-of-art in silico functional assays and had comparable effect sizes to coding variants. A plausible example of new mechanisms of causal variants is an enrichment of causal variants in 3′untranslated regions (UTRs), including the Japanese-specific rs13306436 in IL6 associated with pro-inflammatory traits and protection against tuberculosis. We experimentally showed that transcripts with rs13306436 are resistant to mRNA degradation by regnase-1, an RNA-binding protein. Our study provides a list of fine-mapped causal variants to be tested for functionality and underscores the importance of sequencing, genotyping and association efforts in diverse populations.
摘要：
人类基因变异与许多性状相关，其机制在很大程度上是未知的。研究人员结合约26万名日本研究参与者、日本特异性基因型参考面板和统计精细图谱，在63个数量性状中发现了4423个显著位点，其中601个是新位点，9406个是潜在的因果变异。新的关联包括日本人群特异性的编码、剪接和非编码变异，例如TNNT2基因中的一个有害错义变异rs730881101，其与较低的心脏功能和心力衰竭风险增加有关（P = 1.4×10-15和比值比=4.5，95%置信区间= 3.1-6.5）。潜在的因果非编码变异得到了最先进的计算机功能测试的支持，其效应大小与编码变异相当。因果变异新机制的一个可信例子是，3′非翻译区（UTRs）中的因果变异富集，包括日本特异的IL6基因中的rs13306436，它与促炎症性状和结核病保护相关。实验表明，带有rs13306436的转录本能抵抗RNA结合蛋白regnase-1对mRNA的降解。这一研究提供了一份待测试功能的精细映射因果变异列表，并强调了在不同人群中进行测序、基因分型和关联工作的重要性。
2.Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations
对来自不同人群的29745名发育障碍患者的常染色体隐性编码变异进行联合分析
英国欣克斯顿惠康基因组研究所桑格研究所等合作发表
Abstract:
Autosomal recessive coding variants are well-known causes of rare disorders. We quantified the contribution of these variants to developmental disorders in a large, ancestrally diverse cohort comprising 29,745 trios, of whom 20.4% had genetically inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide autosomal recessive coding variants ranged from 2-19% across genetically inferred ancestry groups and was significantly correlated with average autozygosity. Established autosomal recessive developmental disorder-associated (ARDD) genes explained 84.0% of the total autosomal recessive coding burden, and 34.4% of the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. Statistical analyses identified two novel ARDD genes: KBTBD2 and ZDHHC16. This study expands our understanding of the genetic architecture of developmental disorders across diverse genetically inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may help diagnose more patients than discovering the remaining genes.
摘要：
常染色体隐性编码变异是罕见疾病常见原因。研究人员在一个由29745人组成的大型的血统多样性队列中量化了这些变异对发育障碍的贡献，其中20.4%为非欧洲血统的遗传推断。据估计，可归因于外显子组范围常染色体隐性编码变异的患者比例估计在2%-19%之间，与平均自体同源性显著相关。已知的常染色体隐性发育障碍相关（ARDD）基因解释了总常染色体隐性编码负担的84.0%，而这些已知基因中，34.4%的负担是ClinVar数据库中未报告的致病变异。统计分析确定了两个新的ARDD基因：KBTBD2和ZDHHC16。总之，这一研究扩展了人们对不同遗传背景群体发育障碍遗传结构的理解，并表明，与发现剩余基因相比，改进已知ARDD基因错义变异的解读策略可能有助于诊断更多的患者。
3.Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance
1405名人类血液eQTLs和pQTLs的统计和功能精细映射揭示了不同的调控模式和疾病相关性
日本东京大学医学部基因信息学系、大阪大学医学部统计遗传学系等合作发表
Abstract:
Studying the genetic regulation of protein expression (through protein quantitative trait loci (pQTLs)) offers a deeper understanding of regulatory variants uncharacterized by mRNA expression regulation (expression QTLs (eQTLs)) studies. Here we report cis-eQTL and cis-pQTL statistical fine-mapping from 1,405 genotyped samples with blood mRNA and 2,932 plasma samples of protein expression, as part of the Japan COVID-19 Task Force (JCTF). Fine-mapped eQTLs (n = 3,464) were enriched for 932 variants validated with a massively parallel reporter assay. Fine-mapped pQTLs (n = 582) were enriched for missense variations on structured and extracellular domains, although the possibility of epitope-binding artifacts remains. Trans-eQTL and trans-pQTL analysis highlighted associations of class I HLA allele variation with KIR genes. We contrast the multi-tissue origin of plasma protein with blood mRNA, contributing to the limited colocalization level, distinct regulatory mechanisms and trait relevance of eQTLs and pQTLs. We report a negative correlation between ABO mRNA and protein expression because of linkage disequilibrium between distinct nearby eQTLs and pQTLs.
摘要：
研究蛋白质表达的遗传调控（通过蛋白质定量性状位点（pQTL））能够更深入地理解mRNA表达调控（eQTL）研究未表征的调控变体。本研究基于日本COVID-19工作组（JCTF）的研究报告了1405例基因分型样本的血液mRNA和2932例血浆样本的蛋白质表达的cis-eQTL和cis-pQTL统计精细映射。精细映射的eQTL（n=3464）在大规模平行报告基因检测中得到验证的932个变异中富集。精细映射的pQTL（n=582）在结构域和细胞外域上的错义变异中富集，尽管仍存在表位结合伪影的可能性。Trans-eQTL和Trans-pQTL分析突出了I类HLA等位基因变异与KIR基因之间的关联。研究人员对比了血浆蛋白与血液mRNA的多组织来源，阐明了eQTL和pQTL的有限共定位水平、不同的调控机制和性状相关性。此外，由于不同的邻近eQTL和pQTL之间的连锁不平衡，本研究还报告了ABO基因 mRNA与蛋白质表达之间的负相关性。
4.Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk
系统性优先排序结直肠癌风险的功能变异和效应基因
英国萨顿癌症研究所遗传学和流行病学部、英国爱丁堡大学遗传学与癌症研究所爱丁堡癌症研究中心结肠癌遗传学小组合作发表
Abstract:
Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer–gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment.
摘要：
结直肠癌（CRC）的全基因组关联研究已确定170个常染色体风险位点。然而，其中大多数的功能变异及其目标基因是未知的。研究人员进行统计精细映射，结合组织特异性表观遗传注释和大规模平行报告基因检测，以系统地确定每个CRC风险位点的功能变异的优先级。研究人员确定了170个风险位点的可能因果变异，其中40个位点仅关联1个变异。通过分析结肠特异性定量性状位点（QTLs）并应用Activity-by-Contact模型（结合表观基因组特征和Micro-C数据预测增强子-基因连接），本研究将这些变异与208个靶基因联系起来。通过解析CRC风险位点，本研究解读了风险变异与靶基因之间的直接联系，进一步深入了解CRC易感性的分子机制，并突出了预防和治疗的潜在药物靶点。
5.Five latent factors underlie response to immunotherapy
五个潜在因素影响免疫治疗反应
西班牙巴塞罗那科技学院生物医学研究所、荷兰阿姆斯特丹哈特维格医疗基金会等合作发表
Abstract:
Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we currently ignore how many truly independent biomarkers there are. With an unbiased analysis of genomics, transcriptomics and clinical data of a cohort of patients with metastatic tumors (n = 479), we discovered five orthogonal latent factors: tumor mutation burden, T cell effective infiltration, transforming growth factor-beta activity in the microenvironment, prior treatment and tumor proliferative potential. Their association with CPI response and survival was observed across all tumor types and validated across six independent cohorts (n = 1,491). These five latent factors constitute a frame of reference to organize current and future knowledge on biomarkers of CPI response and survival.
摘要：
只有一部分接受免疫检查点抑制剂（CPI）治疗的患者对治疗有反应，区分反应者与无反应者是一项重大挑战。不同研究中提出许多的生物标志物可能代表相同潜在因素的不同版本。因此，目前仍不清楚有多少真正独立的生物标志物。通过对一组转移性肿瘤患者（n = 479）的基因组学、转录组学和临床数据进行无偏倚分析，研究人员发现了五个独立的潜在因素：肿瘤突变负荷、T 细胞有效浸润、肿瘤微环境中转化生长因子-β的活性、既往治疗和肿瘤增殖潜力。在所有分析的肿瘤类型中都观察到它们与CPI反应和生存率的相关性，并在6个独立队列（n = 1491）中得到验证。这五个潜在因素构成了一个参考框架，用于组织当前和未来关于CPI反应和生存的生物标志物知识。
6.MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution
MHC Hammer 识别癌症进化中的遗传性和非遗传性HLA破坏
英国伦敦弗朗西斯-克里克研究所癌症进化与基因组不稳定性实验室、伦敦大学癌症研究所英国癌症研究中心肺癌卓越中心癌症基因组进化研究小组等合作发表
Abstract:
Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution.
摘要：
I 类人类白细胞抗原（HLA）分子的破坏对免疫逃逸和肿瘤进化具有重要意义。研究人员开发了主要组织相容性复合物杂合性缺失（LOH）、等位基因特异性突变以及表达和抑制测量（MHC Hammer）。结果发现了正常肺和乳腺组织中广泛的HLA等位基因变异和普遍的HLA可变剪接。在肺TRACERx和肺和乳腺TCGA队列中，61%的肺腺癌（LUAD）、76%的肺鳞状细胞癌（LUSC）和35%的雌激素受体阳性（ER+）癌症中发生了I类HLA转录抑制，而在LUAD、 LUSC和ER+癌症中，分别有31%、11%和15%的肿瘤富含HLA可变剪接。与HLA功能障碍在肿瘤进化中的重要性一致，在LUAD中，HLA LOH与转移相关，LUAD原发肿瘤区域中播散转移的区域比未播散区域的有效新抗原负担更低。这些数据突显了HLA转录组破坏（转录抑制和可变剪接）在癌症进化中的广泛性和重要性。
7.NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis
NSD2是促进前列腺癌发生发展的AR/FOXA1新增强子复合体的关键亚基
美国密歇根大学密歇根转化病理学中心、密歇根大学病理学系、密歇根大学罗杰尔癌症中心等联合发表
Abstract:
Androgen receptor (AR) is a ligand-responsive transcription factor that drives terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to activate malignant phenotypes, the molecular mechanisms of which remain unknown. Here, we show that tumor-specific AR enhancers are critically reliant on H3K36 dimethyltransferase activity of NSD2. NSD2 expression is abnormally induced in prostate cancer, where its inactivation impairs AR transactivation potential by disrupting over 65% of its cistrome. NSD2-dependent AR sites distinctively harbor the chimeric FOXA1:AR half-motif, which exclusively comprise tumor-specific AR enhancer circuitries defined from patient specimens. NSD2 inactivation also engenders increased dependency on the NSD1 paralog, and a dual NSD1/2 PROTAC degrader is preferentially cytotoxic in AR-dependent prostate cancer models. Altogether, we characterize NSD2 as an essential AR neo-enhanceosome subunit that enables its oncogenic activity, and position NSD1/2 as viable co-targets in advanced prostate cancer.
摘要：
雄激素受体（AR）是一种配体响应的转录因子，与增强子结合以驱动前列腺管腔上皮细胞的终末分化。然而，在前列腺癌细胞中，AR活性被广泛重新编程以维持恶性表型，其分子机制尚不清楚。本研究表明AR的肿瘤特异性增强子复合体依赖于NSD2的活性。NSD2在前列腺癌细胞中表达异常增加，其失活会通过破坏超过65%的AR染色体结合区域（cistrome）而削弱AR的转录激活能力。NSD2依赖的AR结合位点显著富集嵌合的FOXA1：AR半位点，这些位点组成了从患者样本中定义的肿瘤特异性AR增强子回路。NSD2失活还会导致对NSD1旁系同源基因的依赖性增加，而双靶向NSD1/2的PROTAC降解剂在AR依赖型前列腺癌模型中具有选择性细胞毒性。本研究表征了具有致癌活性的NSD2为AR新型增强体的关键亚基，并将NSD1/2定位为晚期前列腺癌的潜在共靶点。
Volume 56 Issue 11, November 2024
在2024年8月，Nature Genetics共发表42篇文章，其中包括Comment 2篇，Research Highlights 7篇，News & Views 2篇，Research Briefings 4篇，Perspectives 1篇，Articles 22篇，Amendments & Corrections 4篇。主要内容包括全外显子结合阵列和填补分析、罕见编码变异分析、癌症耐药机制等内容。
Yield of genetic association signals from genomes, exomes and imputation in the UK Biobank
英国生物银行中基因组、外显子组和归因的遗传关联信号产出
美国纽约州塔里敦再生基因中心、瑞士洛桑大学计算生物学系合作发表
Abstract:
Whole-genome sequencing (WGS), whole-exome sequencing (WES) and array genotyping with imputation (IMP) are common strategies for assessing genetic variation and its association with medically relevant phenotypes. To date, there has been no systematic empirical assessment of the yield of these approaches when applied to hundreds of thousands of samples to enable the discovery of complex trait genetic signals. Using data for 100 complex traits from 149,195 individuals in the UK Biobank, we systematically compare the relative yield of these strategies in genetic association studies. We find that WGS and WES combined with arrays and imputation (WES+IMP) have the largest association yield. Although WGS results in an approximately fivefold increase in the total number of assayed variants over WES+IMP, the number of detected signals differed by only 1% for both single-variant and gene-based association analyses. Given that WES+IMP typically results in savings of lab and computational time and resources expended per sample, we evaluate the potential benefits of applying WES+IMP to larger samples. When we extend our WES+IMP analyses to 468,169 UK Biobank individuals, we observe an approximately fourfold increase in association signals with the threefold increase in sample size. We conclude that prioritizing WES+IMP and large sample sizes rather than contemporary short-read WGS alternatives will maximize the number of discoveries in genetic association studies.
摘要：
全基因组测序（WGS）、全外显子测序（WES）和基于阵列的基因分型与填补分析（IMP）是评估遗传变异及其与医学相关表型关联的常见策略。迄今为止，尚未对这些方法在数十万样本中的产出进行系统的实证评估，以促进复杂性状遗传信号的发现。利用来自英国生物银行的149195名个体的100个复杂性状数据，系统比较了这些策略在遗传关联研究中的相对产出。研究人员发现，WGS和结合阵列和填补分析的WES（WES+IMP）具有最大的关联产出。尽管WGS使得检测的变异总数相比WES+IMP增加了约五倍，但在单变异和基因基础关联分析中检测到的信号仅相差1%。考虑到WES+IMP通常能节省每个样本的实验和计算时间及资源，研究人员评估了将WES+IMP应用于更大样本的潜在收益。当研究人员将WES+IMP分析扩展到468169名英国生物银行个体时，观察到关联信号约增加四倍，而样本量增加三倍。研究人员得出结论，与目前的短读长WGS替代方法相比，优先采用WES+IMP和扩大样本规模将最大化遗传关联研究中的发现数量。
2.Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes
对51256例2型糖尿病病例和370487例对照的罕见变异分析揭示了单基因糖尿病基因的致病性谱
美国马萨诸塞州哈佛和麻省理工学院布罗德研究所新陈代谢和医学与人口遗传学项目、美国马萨诸塞州麻省总医院基因组医学中心等合作发表
Abstract:
Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels’ limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5×10−5. We identified 12 new variants, including a rare African/African American-enriched enhancer variant near the LEP gene (rs147287548), associated with fourfold increased T2D risk. We also identified a rare missense variant in HNF4A (p.Arg114Trp), associated with eightfold increased T2D risk, previously reported in maturity-onset diabetes of the young with reduced penetrance, but observed here in a T2D GWAS. We further leveraged these data to analyze 1,634 ClinVar variants in 22 genes related to monogenic diabetes, identifying two additional rare variants in HNF1A and GCK associated with fivefold and eightfold increased T2D risk, respectively, the effects of which were modified by the individual’s polygenic risk score. For 21% of the variants with conflicting interpretations or uncertain significance in ClinVar, we provided support of being benign based on their lack of association with T2D. Our work provides a framework for using rare variant GWASs to identify large-effect variants and assess variant pathogenicity in monogenic diabetes genes.
摘要：
2型糖尿病（T2D）的全基因组关联研究（GWAS）通常由于此前推算面板的局限性和全基因组测序（WGS）数据的稀缺而忽视了稀有变异。研究人员使用TOPMed插补和WGS，开展了迄今最大规模的T2D GWAS meta分析，涉及51,256例T2D和370,487例对照，目标变异的次等位基因频率低至5×10⁻⁵。本研究鉴定了12个新变异，包括一个富集于非洲/非裔美国人群的位于LEP基因附近的稀有增强子变异（rs147287548），其与T2D风险增加四倍相关。研究人员还在HNF4A基因中一个稀有错义变异（p.Arg114Trp），该变异与T2D风险增加八倍相关，之前曾在青年发病型糖尿病中报道但具有低外显率，而在本研究的T2D GWAS中首次观察到。研究者进一步利用这些数据分析了与单基因糖尿病相关的22个基因中的1,634个ClinVar变异，鉴定了HNF1A和GCK中另外两个罕见变异，分别与T2D风险增加5倍和8倍相关，其效应受个体多基因风险评分的修饰。对于ClinVar中21%的解释冲突或意义不确定的变异，本研究基于其与T2D缺乏关联提供了其为良性变异的支持证据。本研究为使用罕见变异GWAS来识别大效应变异和评估单基因糖尿病基因中的变异致病性提供了一个框架。
3.Multivariate genomic analysis of 5 million people elucidates the genetic architecture of shared components of the metabolic syndrome
对500万人的多变量基因组分析阐明了代谢综合征共享成分的遗传结构
韩国成均馆大学三星高级健康科学与技术研究所（SAIHST）数字健康部、三星医疗中心、韩国首尔大学盆唐医院神经精神病学系等合作发表
Abstract:
Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (nobserved=4,947,860) by leveraging genetic correlation between MetS components. We identified 1,307 genetic loci associated with MetS that were enriched primarily in brain tissues. Using transcriptomic data, we identified 11 genes associated strongly with MetS. Our phenome-wide association and Mendelian randomization analyses highlighted associations of MetS with diverse diseases beyond cardiometabolic diseases. Polygenic risk score analysis demonstrated better discrimination of MetS and predictive power in European and East Asian populations. Altogether, our findings will guide future studies aimed at elucidating the genetic architecture of MetS.
摘要：
代谢综合征（MetS）是一种复杂的遗传性疾病，包括各种代谢特征作为危险因素。尽管已经通过大规模的全基因组关联研究积极地研究了单个MetS成分的遗传学，但其联合遗传结构尚未完全阐明。研究人员利用MetS组分之间的遗传相关性，在欧洲进行了最大的MetS多变量全基因组关联研究（n=4947860）。确定了1307个与MetS相关的遗传位点，这些位点主要富集在脑组织中。使用转录组数据，研究者确定了11个与MetS密切相关的基因。通过表型组范围关联和孟德尔随机化分析强调了MetS与心脏代谢疾病以外的多种疾病的关联。多基因风险评分分析表明，在欧洲和东亚人群中，MetS的区分度和预测能力更好。总之，此研究结果将指导未来旨在阐明MetS遗传结构的研究。
4.GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia
神经病理学内表型GWSA研究揭示新的疾病风险基因位点
美国肯塔基大学公共卫生学院生物统计学系、大学桑德斯-布朗老龄化中心和阿尔茨海默病研究中心等合作发表
Abstract:
Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer’s Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n=7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.
摘要：
GWAS鉴定了超过80个ADRD的潜在风险基因位点。然而，之前大多数研究中使用的临床结果，掩盖了潜在神经病理学的复杂基因位点。研究人员对11种与阿尔茨海默病及相关痴呆症（ADRD）的神经病理学内表型进行了GWAS分析，参与者有以下三个来源：美国国家阿尔茨海默症协调中心、宗教秩序研究和拉什记忆与衰老项目以及成人思维变化研究（n=7804）。研究发现了八个独立的与ADRD显著相关的位点，其中四个是新的基因位点（COL4A1、PIK3R5、LZTS1和APOC2）。在对已知的ADRD基因位点进行单独检测后，有19个基因位点与至少一种神经病理学有明显相关性。遗传共定位分析确定了多效应和数量性状位点。大脑皮层APOC2附近两个位点的甲基化与脑淀粉样血管病相关。对神经病理学内表型的研究是了解遗传性ADRD风险机制的重要一步。
5.Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia
多组学分析确定非裔美国急性髓性白血病患者生存的预测因子
美国俄亥俄州立大学综合癌症中心、荷兰鹿特丹伊拉斯谟医学中心细胞生物学系等合作发表
Abstract:
Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected. Black patients with myelodysplasia-related AML were younger than white patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable analyses of Black patients, NPM1 and NRAS mutations were associated with inferior disease-free and IDH1 and IDH2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic risk stratification changed risk group assignment for one-third of Black patients and improved their outcome prediction.
摘要：
来自具有不同祖先背景的急性髓性白血病（AML）患者的基因组谱和预后生物标志物尚未得到充分研究。研究人员分析了100 名经基因组学证实具有非洲血统（黑人；Alliance）的急性髓性白血病患者的外显子组和转录组，并将他们的体细胞突变频率与323名自我报告为白人（55%为基因组确认的欧洲血统，白人；BeatAML）的AML患者的体细胞突变频率进行了比较。本研究发现，黑人患者中162个反复出现的基因突变中的73%，包括一个此前未报道的PHIP变异（在7%的患者中发现），仅在1名白人患者中被发现或未被检测到。患有骨髓增生异常相关AML的黑人患者比白人患者年轻，提示存在内在和/或外在的致畸应激因子。在黑人患者的多变量分析中，NPM1和NRAS突变与较差的无病生存期相关，IDH1和IDH2突变与较低的总体生存期相关。炎症特征、细胞类型分布和转录谱在具有NPM1突变的黑人和白人患者之间存在差异。将祖先特异性风险标志物纳入2022年欧洲白血病网（European LeukemiaNet）基因风险分层模型，改变了三分之一黑人患者的风险组分配，并改善了其预后预测。
6.Mapping extrachromosomal DNA amplifications during cancer progression
在癌症进展过程中绘制细胞外染色体DNA的扩增图谱
韩国成均馆大学药学院生物制药融合系、成均馆大学药学院生物健康监管科学系等合作发表
Abstract:
To understand the role of extrachromosomal DNA (ecDNA) amplifications in cancer progression, we detected and classified focal amplifications in 8,060 newly diagnosed primary cancers, untreated metastases and heavily pretreated tumors. The ecDNAs were detected at significantly higher frequency in untreated metastatic and pretreated tumors compared to newly diagnosed cancers. Tumors from chemotherapy-pretreated patients showed significantly higher ecDNA frequency compared to untreated cancers. In particular, tubulin inhibition associated with ecDNA increases, suggesting a role for ecDNA in treatment response. In longitudinally matched tumor samples, ecDNAs were more likely to be retained compared to chromosomal amplifications. EcDNAs shared between time points, and ecDNAs in advanced cancers were more likely to harbor localized hypermutation events compared to private ecDNAs and ecDNAs in newly diagnosed tumors. Relatively high variant allele fractions of ecDNA localized hypermutations implicated early ecDNA mutagenesis. Our findings nominate ecDNAs to provide tumors with competitive advantages during cancer progression and metastasis.
摘要：
为了理解染色体外DNA（ecDNA）扩增在癌症进展中的作用，研究人员检测并分类了8060例新诊断的原发性癌症、未经治疗的转移性癌症和经过多次治疗的肿瘤中的局部扩增现象。结果显示，未经治疗的转移性肿瘤和经过多次治疗的肿瘤中ecDNA的检测频率显著高于新诊断的癌症。尤其是化疗后处理的患者，其肿瘤中的ecDNA频率明显高于未经治疗的癌症。此外，微管蛋白抑制与ecDNA的增加相关，提示ecDNA在治疗反应中可能发挥作用。在纵向匹配的肿瘤样本中，ecDNA相较于染色体扩增更可能被保留。共享ecDNA，以及晚期癌症中的ecDNA，比新诊断肿瘤中的ecDNA更容易发生局部高突变事件。ecDNA局部高突变的较高变异等位基因比例暗示了ecDNA早期突变过程。这些研究结果表明，ecDNA可能为肿瘤在癌症进展和转移过程中提供了竞争优势。
7.Base editing screens define the genetic landscape of cancer drug resistance mechanisms
碱基编辑筛选技术定义了癌症药物耐药机制的遗传图谱
英国欣克斯顿惠康桑格研究所转化癌症基因组学、癌症基因组编辑小组等合作发表
Abstract:
Drug resistance is a principal limitation to the long-term efficacy of cancer therapies. Cancer genome sequencing can retrospectively delineate the genetic basis of drug resistance, but this requires large numbers of post-treatment samples to nominate causal variants. Here we prospectively identify genetic mechanisms of resistance to ten oncology drugs from CRISPR base editing mutagenesis screens in four cancer cell lines using a guide RNA library predicted to install 32,476 variants in 11 cancer genes. We identify four functional classes of protein variants modulating drug sensitivity and use single-cell transcriptomics to reveal how these variants operate through distinct mechanisms, including eliciting a drug-addicted cell state. We identify variants that can be targeted with alternative inhibitors to overcome resistance and functionally validate an epidermal growth factor receptor (EGFR) variant that sensitizes lung cancer cells to EGFR inhibitors. Our variant-to-function map has implications for patient stratification, therapy combinations and drug scheduling in cancer treatment.
摘要：
药物耐药性是癌症治疗长期疗效的主要限制因素。癌症基因组测序可以回顾性地描述耐药性的遗传基础，但这需要大量的治疗后样本来指定因果变异。研究人员使用预计在11个癌症基因中安装32,476个变异的导向RNA文库，从四种癌细胞系中的CRISPR碱基编辑诱变筛选中前瞻性地确定了对10种肿瘤药物耐药的遗传机制。本研究确定了调节药物敏感性的蛋白质变体的四种功能类别，并使用单细胞转录组学来揭示这些变体如何通过不同的机制发挥作用，包括引发药物成瘾变体。研究者并确定了可以用替代抑制剂靶向以克服耐药性的变体，并在功能上验证了使肺癌细胞对 EGFR 抑制剂敏感的EGFR变体。这些发现对于癌症治疗中的患者分层、治疗组合和药物安排有重要意义。
汇报人：郝智贞
导师：刘锋、刘吉峰
审核：宋瑶、任建君
