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Methylated GCC repeat expansion in AFF3 associates with intellectual disability AFF3 中甲基化的 GCC 重复扩增与智力残疾有关
IF 31.7 1区 生物学
Nature genetics Pub Date : 2024-09-27 DOI: 10.1038/s41588-024-01918-0
{"title":"Methylated GCC repeat expansion in AFF3 associates with intellectual disability","authors":"","doi":"10.1038/s41588-024-01918-0","DOIUrl":"10.1038/s41588-024-01918-0","url":null,"abstract":"We identified methylated tandem repeat expansions that resemble the FMR1 CGG repeat that causes fragile X syndrome and investigated their association with traits in the UK Biobank. AFF3 expansion carriers had a 2.4-fold reduced probability of completing secondary education and were enriched in a cohort of individuals with intellectual disability.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2302-2303"},"PeriodicalIF":31.7,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Long-term 3D primary epithelioid cultures reveal genes that regulate esophageal cell fitness 长期三维原代上皮细胞培养揭示调控食管细胞健康的基因
IF 31.7 1区 生物学
Nature genetics Pub Date : 2024-09-27 DOI: 10.1038/s41588-024-01887-4
{"title":"Long-term 3D primary epithelioid cultures reveal genes that regulate esophageal cell fitness","authors":"","doi":"10.1038/s41588-024-01887-4","DOIUrl":"10.1038/s41588-024-01887-4","url":null,"abstract":"Primary cell cultures need to be frequently passaged, which limits the study of long-term biological processes, such as how mutant clones colonize aging epithelia. Esophageal epithelioids self-maintain for months, recapitulating progenitor cell behavior in vivo. Epithelioid CRISPR–Cas9 screens reveal genes encoding molecules that control cell fitness.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2010-2011"},"PeriodicalIF":31.7,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Publisher Correction: Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance 出版商更正:来自1405名人类的血液eQTL和pQTL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
IF 31.7 1区 生物学
Nature genetics Pub Date : 2024-09-27 DOI: 10.1038/s41588-024-01959-5
Qingbo S. Wang, Takanori Hasegawa, Ho Namkoong, Ryunosuke Saiki, Ryuya Edahiro, Kyuto Sonehara, Hiromu Tanaka, Shuhei Azekawa, Shotaro Chubachi, Yugo Takahashi, Saori Sakaue, Shinichi Namba, Kenichi Yamamoto, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Hideki Makishima, Yasuhito Nannya, Zicong Zhang, Rika Tsujikawa, Ryuji Koike, Tomomi Takano, Makoto Ishii, Akinori Kimura, Fumitaka Inoue, Takanori Kanai, Koichi Fukunaga, Seishi Ogawa, Seiya Imoto, Satoru Miyano, Yukinori Okada, Japan COVID-19 Task Force
{"title":"Publisher Correction: Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance","authors":"Qingbo S. Wang, Takanori Hasegawa, Ho Namkoong, Ryunosuke Saiki, Ryuya Edahiro, Kyuto Sonehara, Hiromu Tanaka, Shuhei Azekawa, Shotaro Chubachi, Yugo Takahashi, Saori Sakaue, Shinichi Namba, Kenichi Yamamoto, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Hideki Makishima, Yasuhito Nannya, Zicong Zhang, Rika Tsujikawa, Ryuji Koike, Tomomi Takano, Makoto Ishii, Akinori Kimura, Fumitaka Inoue, Takanori Kanai, Koichi Fukunaga, Seishi Ogawa, Seiya Imoto, Satoru Miyano, Yukinori Okada, Japan COVID-19 Task Force","doi":"10.1038/s41588-024-01959-5","DOIUrl":"10.1038/s41588-024-01959-5","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2281-2281"},"PeriodicalIF":31.7,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01959-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Context-specific targeting of the androgen receptor in prostate cancer 前列腺癌中雄激素受体的特异性靶向作用
IF 31.7 1区 生物学
Nature genetics Pub Date : 2024-09-27 DOI: 10.1038/s41588-024-01935-z
Cory Abate-Shen
{"title":"Context-specific targeting of the androgen receptor in prostate cancer","authors":"Cory Abate-Shen","doi":"10.1038/s41588-024-01935-z","DOIUrl":"10.1038/s41588-024-01935-z","url":null,"abstract":"A co-factor for the androgen receptor, NSD2, provides insights into context-specific functions of the androgen receptor and is a new target for intervention.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2000-2001"},"PeriodicalIF":31.7,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identifying genetic variants that influence the abundance of cell states in single-cell data 识别影响单细胞数据中细胞状态丰度的基因变异
IF 31.7 1区 生物学
Nature genetics Pub Date : 2024-09-26 DOI: 10.1038/s41588-024-01909-1
Laurie Rumker, Saori Sakaue, Yakir Reshef, Joyce B. Kang, Seyhan Yazar, Jose Alquicira-Hernandez, Cristian Valencia, Kaitlyn A. Lagattuta, Annelise Mah-Som, Aparna Nathan, Joseph E. Powell, Po-Ru Loh, Soumya Raychaudhuri
{"title":"Identifying genetic variants that influence the abundance of cell states in single-cell data","authors":"Laurie Rumker, Saori Sakaue, Yakir Reshef, Joyce B. Kang, Seyhan Yazar, Jose Alquicira-Hernandez, Cristian Valencia, Kaitlyn A. Lagattuta, Annelise Mah-Som, Aparna Nathan, Joseph E. Powell, Po-Ru Loh, Soumya Raychaudhuri","doi":"10.1038/s41588-024-01909-1","DOIUrl":"10.1038/s41588-024-01909-1","url":null,"abstract":"Disease risk alleles influence the composition of cells present in the body, but modeling genetic effects on the cell states revealed by single-cell profiling is difficult because variant-associated states may reflect diverse combinations of the profiled cell features that are challenging to predefine. We introduce Genotype–Neighborhood Associations (GeNA), a statistical tool to identify cell-state abundance quantitative trait loci (csaQTLs) in high-dimensional single-cell datasets. Instead of testing associations to predefined cell states, GeNA flexibly identifies the cell states whose abundance is most associated with genetic variants. In a genome-wide survey of single-cell RNA sequencing peripheral blood profiling from 969 individuals, GeNA identifies five independent loci associated with shifts in the relative abundance of immune cell states. For example, rs3003-T (P = 1.96 × 10−11) associates with increased abundance of natural killer cells expressing tumor necrosis factor response programs. This csaQTL colocalizes with increased risk for psoriasis, an autoimmune disease that responds to anti-tumor necrosis factor treatments. Flexibly characterizing csaQTLs for granular cell states may help illuminate how genetic background alters cellular composition to confer disease risk. GeNA identifies cell-state abundance quantitative trait loci (csaQTLs) in single-cell RNA sequencing data. Applied to OneK1K, GeNA identifies natural killer cell and myeloid csaQTLs and implicates interferon-α-related cell states using a polygenic risk score for systemic lupus erythematosus.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2068-2077"},"PeriodicalIF":31.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Enhancing the Polygenic Score Catalog with tools for score calculation and ancestry normalization 利用分数计算和祖先归一化工具增强多基因分数目录
IF 31.7 1区 生物学
Nature genetics Pub Date : 2024-09-26 DOI: 10.1038/s41588-024-01937-x
Samuel A. Lambert, Benjamin Wingfield, Joel T. Gibson, Laurent Gil, Santhi Ramachandran, Florent Yvon, Shirin Saverimuttu, Emily Tinsley, Elizabeth Lewis, Scott C. Ritchie, Jingqin Wu, Rodrigo Cánovas, Aoife McMahon, Laura W. Harris, Helen Parkinson, Michael Inouye
{"title":"Enhancing the Polygenic Score Catalog with tools for score calculation and ancestry normalization","authors":"Samuel A. Lambert, Benjamin Wingfield, Joel T. Gibson, Laurent Gil, Santhi Ramachandran, Florent Yvon, Shirin Saverimuttu, Emily Tinsley, Elizabeth Lewis, Scott C. Ritchie, Jingqin Wu, Rodrigo Cánovas, Aoife McMahon, Laura W. Harris, Helen Parkinson, Michael Inouye","doi":"10.1038/s41588-024-01937-x","DOIUrl":"10.1038/s41588-024-01937-x","url":null,"abstract":"Polygenic scores (PGSs) have transformed human genetic research and have numerous potential clinical applications. Here we present a series of recent enhancements to the PGS Catalog and highlight the PGS Catalog Calculator, an open-source, scalable and portable pipeline for reproducibly calculating PGSs that democratizes equitable PGS applications.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"1989-1994"},"PeriodicalIF":31.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Host physiology shapes the mutational landscape of normal and carcinogenic tissue 宿主生理决定正常组织和致癌组织的突变情况
IF 31.7 1区 生物学
Nature genetics Pub Date : 2024-09-26 DOI: 10.1038/s41588-024-01922-4
Nadia Nasreddin, Owen J. Sansom
{"title":"Host physiology shapes the mutational landscape of normal and carcinogenic tissue","authors":"Nadia Nasreddin, Owen J. Sansom","doi":"10.1038/s41588-024-01922-4","DOIUrl":"10.1038/s41588-024-01922-4","url":null,"abstract":"Somatic mutations accrue with age as patches of mutant clones arise in otherwise histologically normal tissue. The clones’ persistence, expansion and roles in physiology and tumorigenesis are unclear. New work on the behavior of Pik3caH1047R mutant esophageal clones shows that host-dependent metabolic features underpin their expansion.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2002-2003"},"PeriodicalIF":31.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Spatial mapping of primary and metastatic pancreatic tumor ecosystems 原发性和转移性胰腺肿瘤生态系统的空间分布图
IF 31.7 1区 生物学
Nature genetics Pub Date : 2024-09-26 DOI: 10.1038/s41588-024-01915-3
{"title":"Spatial mapping of primary and metastatic pancreatic tumor ecosystems","authors":"","doi":"10.1038/s41588-024-01915-3","DOIUrl":"10.1038/s41588-024-01915-3","url":null,"abstract":"This study presents a spatial transcriptomic analysis of matched primary tumors, liver metastases and lymph node metastases from patients with pancreatic ductal adenocarcinoma. Using a tumor ecosystem approach, we uncovered notable tumor microenvironmental heterogeneity and marked differences between primary and metastatic samples, providing key insights into metastatic pancreatic cancer.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2306-2307"},"PeriodicalIF":31.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Yield of genetic association signals from genomes, exomes and imputation in the UK Biobank 英国生物库中基因组、外显子组和估算的遗传关联信号的产量
IF 31.7 1区 生物学
Nature genetics Pub Date : 2024-09-25 DOI: 10.1038/s41588-024-01930-4
Sheila M. Gaynor, Tyler Joseph, Xiaodong Bai, Yuxin Zou, Boris Boutkov, Evan K. Maxwell, Olivier Delaneau, Robin J. Hofmeister, Olga Krasheninina, Suganthi Balasubramanian, Anthony Marcketta, Joshua Backman, Regeneron Genetics Center, Jeffrey G. Reid, John D. Overton, Luca A. Lotta, Jonathan Marchini, William J. Salerno, Aris Baras, Goncalo R. Abecasis, Timothy A. Thornton
{"title":"Yield of genetic association signals from genomes, exomes and imputation in the UK Biobank","authors":"Sheila M. Gaynor, Tyler Joseph, Xiaodong Bai, Yuxin Zou, Boris Boutkov, Evan K. Maxwell, Olivier Delaneau, Robin J. Hofmeister, Olga Krasheninina, Suganthi Balasubramanian, Anthony Marcketta, Joshua Backman, Regeneron Genetics Center, Jeffrey G. Reid, John D. Overton, Luca A. Lotta, Jonathan Marchini, William J. Salerno, Aris Baras, Goncalo R. Abecasis, Timothy A. Thornton","doi":"10.1038/s41588-024-01930-4","DOIUrl":"10.1038/s41588-024-01930-4","url":null,"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. Comparison of association signals in UK Biobank using different strategies for assessing genetic variation shows that whole-exome sequencing combined with array genotyping and imputation offers similar performance to whole-genome sequencing at a reduced cost.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2345-2351"},"PeriodicalIF":31.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01930-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Integration of variant annotations using deep set networks boosts rare variant association testing 利用深度集网络整合变异注释可促进罕见变异关联测试
IF 31.7 1区 生物学
Nature genetics Pub Date : 2024-09-25 DOI: 10.1038/s41588-024-01919-z
Brian Clarke, Eva Holtkamp, Hakime Öztürk, Marcel Mück, Magnus Wahlberg, Kayla Meyer, Felix Munzlinger, Felix Brechtmann, Florian R. Hölzlwimmer, Jonas Lindner, Zhifen Chen, Julien Gagneur, Oliver Stegle
{"title":"Integration of variant annotations using deep set networks boosts rare variant association testing","authors":"Brian Clarke, Eva Holtkamp, Hakime Öztürk, Marcel Mück, Magnus Wahlberg, Kayla Meyer, Felix Munzlinger, Felix Brechtmann, Florian R. Hölzlwimmer, Jonas Lindner, Zhifen Chen, Julien Gagneur, Oliver Stegle","doi":"10.1038/s41588-024-01919-z","DOIUrl":"10.1038/s41588-024-01919-z","url":null,"abstract":"Rare genetic variants can have strong effects on phenotypes, yet accounting for rare variants in genetic analyses is statistically challenging due to the limited number of allele carriers and the burden of multiple testing. While rich variant annotations promise to enable well-powered rare variant association tests, methods integrating variant annotations in a data-driven manner are lacking. Here we propose deep rare variant association testing (DeepRVAT), a model based on set neural networks that learns a trait-agnostic gene impairment score from rare variant annotations and phenotypes, enabling both gene discovery and trait prediction. On 34 quantitative and 63 binary traits, using whole-exome-sequencing data from UK Biobank, we find that DeepRVAT yields substantial gains in gene discoveries and improved detection of individuals at high genetic risk. Finally, we demonstrate how DeepRVAT enables calibrated and computationally efficient rare variant tests at biobank scale, aiding the discovery of genetic risk factors for human disease traits. Deep rare variant association testing (DeepRVAT) is a deep set neural network model that flexibly integrates rare variant annotations into a trait-agnostic gene impairment score. These scores improve association testing and polygenic risk prediction.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2271-2280"},"PeriodicalIF":31.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01919-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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