Nature genetics最新文献

{"title":"Genetic insights into depression","authors":"Kyle Vogan","doi":"10.1038/s41588-023-01482-z","DOIUrl":"10.1038/s41588-023-01482-z","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 8","pages":"1253-1253"},"PeriodicalIF":30.8,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10152604","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}

{"title":"Spatial multiomics of the human heart","authors":"Wei Li","doi":"10.1038/s41588-023-01481-0","DOIUrl":"10.1038/s41588-023-01481-0","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 8","pages":"1253-1253"},"PeriodicalIF":30.8,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10152606","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}

{"title":"Genome-wide analysis of a model-derived binge eating disorder phenotype identifies risk loci and implicates iron metabolism","authors":"David Burstein, Trevor C. Griffen, Karen Therrien, Jaroslav Bendl, Sanan Venkatesh, Pengfei Dong, Amirhossein Modabbernia, Biao Zeng, Deepika Mathur, Gabriel Hoffman, Robyn Sysko, Tom Hildebrandt, Georgios Voloudakis, Panos Roussos","doi":"10.1038/s41588-023-01464-1","DOIUrl":"10.1038/s41588-023-01464-1","url":null,"abstract":"Binge eating disorder (BED) is the most common eating disorder, yet its genetic architecture remains largely unknown. Studying BED is challenging because it is often comorbid with obesity, a common and highly polygenic trait, and it is underdiagnosed in biobank data sets. To address this limitation, we apply a supervised machine-learning approach (using 822 cases of individuals diagnosed with BED) to estimate the probability of each individual having BED based on electronic medical records from the Million Veteran Program. We perform a genome-wide association study of individuals of African (n = 77,574) and European (n = 285,138) ancestry while controlling for body mass index to identify three independent loci near the HFE, MCHR2 and LRP11 genes and suggest APOE as a risk gene for BED. We identify shared heritability between BED and several neuropsychiatric traits, and implicate iron metabolism in the pathophysiology of BED. Overall, our findings provide insights into the genetics underlying BED and suggest directions for future translational research. Genome-wide association analysis of a binge eating disorder phenotype derived from a supervised machine-learning model applied to electronic medical records identifies three risk loci for this disorder and implicates iron metabolism in its etiology.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 9","pages":"1462-1470"},"PeriodicalIF":30.8,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10186588","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}

{"title":"Machine learning drives genetic discovery for binge eating disorder","authors":"Jackson G. Thorp, Zachary F. Gerring, Eske M. Derks","doi":"10.1038/s41588-023-01473-0","DOIUrl":"10.1038/s41588-023-01473-0","url":null,"abstract":"Identifying genetic risk factors for binge-eating disorder (BED) is vital to understand its etiology and develop effective prevention and intervention strategies. To overcome under-reporting of clinical BED diagnosis, a new study uses machine learning to identify genetic variants associated with quantitative BED risk scores and finds evidence for a pathological role of heme metabolism.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 9","pages":"1424-1425"},"PeriodicalIF":30.8,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10186587","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}

{"title":"PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework","authors":"Alexander J. M. Dingemans, Max Hinne, Kim M. G. Truijen, Lia Goltstein, Jeroen van Reeuwijk, Nicole de Leeuw, Janneke Schuurs-Hoeijmakers, Rolph Pfundt, Illja J. Diets, Joery den Hoed, Elke de Boer, Jet Coenen-van der Spek, Sandra Jansen, Bregje W. van Bon, Noraly Jonis, Charlotte W. Ockeloen, Anneke T. Vulto-van Silfhout, Tjitske Kleefstra, David A. Koolen, Philippe M. Campeau, Elizabeth E. Palmer, Hilde Van Esch, Gholson J. Lyon, Fowzan S. Alkuraya, Anita Rauch, Ronit Marom, Diana Baralle, Pleuntje J. van der Sluijs, Gijs W. E. Santen, R. Frank Kooy, Marcel A. J. van Gerven, Lisenka E. L. M. Vissers, Bert B. A. de Vries","doi":"10.1038/s41588-023-01469-w","DOIUrl":"10.1038/s41588-023-01469-w","url":null,"abstract":"Several molecular and phenotypic algorithms exist that establish genotype–phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore’s ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype–phenotype studies by testing hypotheses on possible phenotypic (sub)groups. PhenoScore confirmed previously known phenotypic subgroups caused by variants in the same gene for SATB1, SETBP1 and DEAF1 and provides objective clinical evidence for two distinct ADNP-related phenotypes, already established functionally. PhenoScore is an open-source machine-learning tool that combines facial image recognition with Human Phenotype Ontology for genetic syndrome identification without genomic data, with applications to subgroup analysis and variants of unknown significance classification.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 9","pages":"1598-1607"},"PeriodicalIF":30.8,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10186590","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}

{"title":"Somatic mutations in facial skin from countries of contrasting skin cancer risk","authors":"Charlotte King, Joanna C. Fowler, Irina Abnizova, Roshan K. Sood, Michael W. J. Hall, Ildikó Szeverényi, Muly Tham, Jingxiang Huang, Stephanie Ming Young, Benjamin A. Hall, E. Birgitte Lane, Philip H. Jones","doi":"10.1038/s41588-023-01468-x","DOIUrl":"10.1038/s41588-023-01468-x","url":null,"abstract":"The incidence of keratinocyte cancer (basal cell and squamous cell carcinomas of the skin) is 17-fold lower in Singapore than the UK1–3, despite Singapore receiving 2–3 times more ultraviolet (UV) radiation4,5. Aging skin contains somatic mutant clones from which such cancers develop6,7. We hypothesized that differences in keratinocyte cancer incidence may be reflected in the normal skin mutational landscape. Here we show that, compared to Singapore, aging facial skin from populations in the UK has a fourfold greater mutational burden, a predominant UV mutational signature, increased copy number aberrations and increased mutant TP53 selection. These features are shared by keratinocyte cancers from high-incidence and low-incidence populations8–13. In Singaporean skin, most mutations result from cell-intrinsic processes; mutant NOTCH1 and NOTCH2 are more strongly selected than in the UK. Aging skin in a high-incidence country has multiple features convergent with cancer that are not found in a low-risk country. These differences may reflect germline variation in UV-protective genes. A comparison of somatic mutations in skin from individuals from the UK and Singapore suggests that the difference in cancer incidence between the two countries is due to markedly different mutational spectra and patterns of selection.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 9","pages":"1440-1447"},"PeriodicalIF":30.8,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10484783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10186570","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}

{"title":"Our ancestry dictates clonal architecture and skin cancer susceptibility","authors":"Marco De Dominici, James DeGregori","doi":"10.1038/s41588-023-01467-y","DOIUrl":"10.1038/s41588-023-01467-y","url":null,"abstract":"Incidence of keratinocyte skin cancer varies markedly between populations living in different areas of the world. A detailed analysis of somatic mutations in the normal skin of individuals from the UK and Singapore reveals different patterns of clonal mutational landscapes that could contribute to differential risk.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 9","pages":"1428-1429"},"PeriodicalIF":30.8,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10186569","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}

{"title":"SF3B1-mutant cells succumb to replication stress under PARP inhibition","authors":"","doi":"10.1038/s41588-023-01461-4","DOIUrl":"10.1038/s41588-023-01461-4","url":null,"abstract":"Across multiple cancer types, hotspot mutations in SF3B1 confer selective sensitivity to multiple clinically available PARP inhibitors. This sensitivity is due to reduced levels of CINP specifically in SF3B1-mutant cells, which leads to a loss of the canonical replication stress response after challenge with PARP inhibitors.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 8","pages":"1265-1266"},"PeriodicalIF":30.8,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10149172","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}

{"title":"Author Correction: HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription","authors":"Peng Huang, Scott A. Peslak, Ren Ren, Eugene Khandros, Kunhua Qin, Cheryl A. Keller, Belinda Giardine, Henry W. Bell, Xianjiang Lan, Malini Sharma, John R. Horton, Osheiza Abdulmalik, Stella T. Chou, Junwei Shi, Merlin Crossley, Ross C. Hardison, Xiaodong Cheng, Gerd A. Blobel","doi":"10.1038/s41588-023-01488-7","DOIUrl":"10.1038/s41588-023-01488-7","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 9","pages":"1608-1608"},"PeriodicalIF":30.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-023-01488-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10241410","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}

{"title":"SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response","authors":"Philip Bland, Harry Saville, Patty T. Wai, Lucinda Curnow, Gareth Muirhead, Jadwiga Nieminuszczy, Nivedita Ravindran, Marie Beatrix John, Somaieh Hedayat, Holly E. Barker, James Wright, Lu Yu, Ioanna Mavrommati, Abigail Read, Barrie Peck, Mark Allen, Patrycja Gazinska, Helen N. Pemberton, Aditi Gulati, Sarah Nash, Farzana Noor, Naomi Guppy, Ioannis Roxanis, Guy Pratt, Ceri Oldreive, Tatjana Stankovic, Samantha Barlow, Helen Kalirai, Sarah E. Coupland, Ronan Broderick, Samar Alsafadi, Alexandre Houy, Marc-Henri Stern, Stephen Pettit, Jyoti S. Choudhary, Syed Haider, Wojciech Niedzwiedz, Christopher J. Lord, Rachael Natrajan","doi":"10.1038/s41588-023-01460-5","DOIUrl":"10.1038/s41588-023-01460-5","url":null,"abstract":"SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population. SF3B1 mutations confer sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). Mechanistically, this is independent of homologous recombination repair and instead relies on a defective replication stress response due to a reduction of the cyclin-dependent kinase 2 interacting protein (CINP). PARPi treatment of SF3B1 mutant (SF3B1MUT) tumors leads to replication stress induced by increased fork origin firing and culminates in cell cycle stalling.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 8","pages":"1311-1323"},"PeriodicalIF":30.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10147230","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}