Nature genetics最新文献

{"title":"Autoreactive T cells target neoself-antigens in lupus","authors":"Kyle Vogan","doi":"10.1038/s41588-024-01955-9","DOIUrl":"10.1038/s41588-024-01955-9","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"1999-1999"},"PeriodicalIF":31.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398525","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":"Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides","authors":"Marketa Tomkova, Michael John McClellan, Gilles Crevel, Akbar Muhammed Shahid, Nandini Mozumdar, Jakub Tomek, Emelie Shepherd, Sue Cotterill, Benjamin Schuster-Böckler, Skirmantas Kriaucionis","doi":"10.1038/s41588-024-01945-x","DOIUrl":"10.1038/s41588-024-01945-x","url":null,"abstract":"C-to-T transitions in CpG dinucleotides are the most prevalent mutations in human cancers and genetic diseases. These mutations have been attributed to deamination of 5-methylcytosine (5mC), an epigenetic modification found on CpGs. We recently linked CpG>TpG mutations to replication and hypothesized that errors introduced by polymerase ε (Pol ε) may represent an alternative source of mutations. Here we present a new method called polymerase error rate sequencing (PER-seq) to measure the error spectrum of DNA polymerases in isolation. We find that the most common human cancer-associated Pol ε mutant (P286R) produces an excess of CpG>TpG errors, phenocopying the mutation spectrum of tumors carrying this mutation and deficiencies in mismatch repair. Notably, we also discover that wild-type Pol ε has a sevenfold higher error rate when replicating 5mCpG compared to C in other contexts. Together, our results from PER-seq and human cancers demonstrate that replication errors are a major contributor to CpG>TpG mutagenesis in replicating cells, fundamentally changing our understanding of this important disease-causing mutational mechanism. A new method called polymerase error rate sequencing (PER-seq) can measure the nucleotide misincorporation rate of DNA polymerases. DNA polymerase ε mutants produce an excess of CpG","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2506-2516"},"PeriodicalIF":31.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01945-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397747","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":"Defining genome access of transcription factors","authors":"Petra Gross","doi":"10.1038/s41588-024-01953-x","DOIUrl":"10.1038/s41588-024-01953-x","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"1999-1999"},"PeriodicalIF":31.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398333","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":"DNA polymerase ε produces elevated C-to-T mutations at methylated CpG dinucleotides","authors":"","doi":"10.1038/s41588-024-01946-w","DOIUrl":"10.1038/s41588-024-01946-w","url":null,"abstract":"C-to-T mutations in CpG dinucleotides are widespread in cancers and are also observed in normal cells. By developing and using a technique to quantify DNA polymerase errors (polymerase error rate sequencing, PER-seq), we reveal that C-to-T mutations in CpG dinucleotides constitute part of the error signature of both wild-type and mutant cancer-associated DNA polymerase ε.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2304-2305"},"PeriodicalIF":31.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391958","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":"GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia","authors":"Lincoln M. P. Shade, Yuriko Katsumata, Erin L. Abner, Khine Zin Aung, Steven A. Claas, Qi Qiao, Bernardo Aguzzoli Heberle, J. Anthony Brandon, Madeline L. Page, Timothy J. Hohman, Shubhabrata Mukherjee, Richard P. Mayeux, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, Walter A. Kukull, Kwangsik Nho, Andrew J. Saykin, David A. Bennett, Julie A. Schneider, The National Alzheimer’s Coordinating Center, Mark T. W. Ebbert, Peter T. Nelson, David W. Fardo","doi":"10.1038/s41588-024-01939-9","DOIUrl":"10.1038/s41588-024-01939-9","url":null,"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. Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2407-2421"},"PeriodicalIF":31.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01939-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384361","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":"Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes","authors":"Alicia Huerta-Chagoya, Philip Schroeder, Ravi Mandla, Jiang Li, Lowri Morris, Maheak Vora, Ahmed Alkanaq, Dorka Nagy, Lukasz Szczerbinski, Jesper G. S. Madsen, Silvia Bonàs-Guarch, Fanny Mollandin, Joanne B. Cole, Bianca Porneala, Kenneth Westerman, Josephine H. Li, Toni I. Pollin, Jose C. Florez, Anna L. Gloyn, David J. Carey, Inês Cebola, Uyenlinh L. Mirshahi, Alisa K. Manning, Aaron Leong, Miriam Udler, Josep M. Mercader","doi":"10.1038/s41588-024-01947-9","DOIUrl":"10.1038/s41588-024-01947-9","url":null,"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. Rare variant analyses identify a new type 2 diabetes risk allele near the LEP gene, which encodes leptin, and other risk alleles of intermediate penetrance in genes previously implicated in monogenic forms of diabetes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2370-2379"},"PeriodicalIF":31.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01947-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384474","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":"Genetic architecture reconciles linkage and association studies of complex traits","authors":"Julia Sidorenko, Baptiste Couvy-Duchesne, Kathryn E. Kemper, Gunn-Helen Moen, Laxmi Bhatta, Bjørn Olav Åsvold, Reedik Mägi, Estonian Biobank Research Team, Alireza Ani, Rujia Wang, Ilja M. Nolte, Lifelines Cohort Study, Scott Gordon, Caroline Hayward, Archie Campbell, Daniel J. Benjamin, David Cesarini, David M. Evans, Michael E. Goddard, Chris S. Haley, David Porteous, Sarah E. Medland, Nicholas G. Martin, Harold Snieder, Andres Metspalu, Kristian Hveem, Ben Brumpton, Peter M. Visscher, Loic Yengo","doi":"10.1038/s41588-024-01940-2","DOIUrl":"10.1038/s41588-024-01940-2","url":null,"abstract":"Linkage studies have successfully mapped loci underlying monogenic disorders, but mostly failed when applied to common diseases. Conversely, genome-wide association studies (GWASs) have identified replicable associations between thousands of SNPs and complex traits, yet capture less than half of the total heritability. In the present study we reconcile these two approaches by showing that linkage signals of height and body mass index (BMI) from 119,000 sibling pairs colocalize with GWAS-identified loci. Concordant with polygenicity, we observed the following: a genome-wide inflation of linkage test statistics; that GWAS results predict linkage signals; and that adjusting phenotypes for polygenic scores reduces linkage signals. Finally, we developed a method using recombination rate-stratified, identity-by-descent sharing between siblings to unbiasedly estimate heritability of height (0.76 ± 0.05) and BMI (0.55 ± 0.07). Our results imply that substantial heritability remains unaccounted for by GWAS-identified loci and this residual genetic variation is polygenic and enriched near these loci. Analyses of height and body mass index in 119,000 sibling pairs show that linkage and genome-wide association signals colocalize. Further analyses suggest that family-based linkage signals are fully consistent with a highly polygenic architecture.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2352-2360"},"PeriodicalIF":31.7,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383640","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":"Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia","authors":"Andrew Stiff, Maarten Fornerod, Bailee N. Kain, Deedra Nicolet, Benjamin J. Kelly, Katherine E. Miller, Krzysztof Mrózek, Isaiah Boateng, Audrey Bollas, Elizabeth A. R. Garfinkle, Omolegho Momoh, Foluke A. Fasola, Hannah O. Olawumi, Nuria Mencia-Trinchant, Jean F. Kloppers, Anne-Cecilia van Marle, Eileen Hu, Saranga Wijeratne, Gregory Wheeler, Christopher J. Walker, Jill Buss, Adrienne Heyrosa, Helee Desai, Andrea Laganson, Ethan Hamp, Yazan Abu-Shihab, Hasan Abaza, Parker Kronen, Sidharth Sen, Megan E. Johnstone, Kate Quinn, Ben Wronowski, Erin Hertlein, Linde A. Miles, Alice S. Mims, Christopher C. Oakes, James S. Blachly, Karilyn T. Larkin, Bethany Mundy-Bosse, Andrew J. Carroll, Bayard L. Powell, Jonathan E. Kolitz, Richard M. Stone, Cassandra Duarte, Diana Abbott, Maria L. Amaya, Craig T. Jordan, Geoffrey L. Uy, Wendy Stock, Kellie J. Archer, Electra D. Paskett, Monica L. Guzman, Ross L. Levine, Kamal Menghrajani, Debyani Chakravarty, Michael F. Berger, Daniel Bottomly, Shannon K. McWeeney, Jeffrey W. Tyner, John C. Byrd, Nathan Salomonis, H. Leighton Grimes, Elaine R. Mardis, Ann-Kathrin Eisfeld","doi":"10.1038/s41588-024-01929-x","DOIUrl":"10.1038/s41588-024-01929-x","url":null,"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. Analysis of exomes and transcriptomes from 100 African American patients with acute myeloid leukemia identifies ancestry-related variation in mutation profiles and survival. Refined risk classification suggests clinical relevance of these ancestry-associated differences.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2434-2446"},"PeriodicalIF":31.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01929-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369986","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":"Genetic African ancestry modifies the biology of acute myeloid leukemia","authors":"Evelyn M. Jiagge","doi":"10.1038/s41588-024-01869-6","DOIUrl":"10.1038/s41588-024-01869-6","url":null,"abstract":"African American patients were under-represented in the studies that led to the current patient classification system for acute myeloid leukemia (AML). A new in-depth analysis of the genetics of AML in African Americans suggests that this omission has implications for patient care.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2299-2301"},"PeriodicalIF":31.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369985","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":"Population-specific putative causal variants shape quantitative traits","authors":"Satoshi Koyama, Xiaoxi Liu, Yoshinao Koike, Keiko Hikino, Masaru Koido, Wei Li, Kotaro Akaki, Kohei Tomizuka, Shuji Ito, Nao Otomo, Hiroyuki Suetsugu, Soichiro Yoshino, Masato Akiyama, Kohei Saito, Yuki Ishikawa, Christian Benner, Pradeep Natarajan, Patrick T. Ellinor, Taisei Mushiroda, Momoko Horikoshi, Masashi Ikeda, Nakao Iwata, Koichi Matsuda, Biobank Japan Project, Shumpei Niida, Kouichi Ozaki, Yukihide Momozawa, Shiro Ikegawa, Osamu Takeuchi, Kaoru Ito, Chikashi Terao","doi":"10.1038/s41588-024-01913-5","DOIUrl":"10.1038/s41588-024-01913-5","url":null,"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. Genome-wide association and fine-mapping analyses in approximately 260,000 Japanese individuals combined with a newly constructed Japanese-specific genotype reference panel identify hundreds of new loci and putative causal variants for 63 quantitative traits.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2027-2035"},"PeriodicalIF":31.7,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01913-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142368959","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}