Recent observational studies have found an association between Clonal Hematopoesis (CH) and strokes but with incomplete results. This study aims to comprehensively characterize mutation-specific effects of CH on ischemic and hemorrhagic stroke subtypes and 90-day functional outcomes through publicly available genome-wide association study (GWAS) cohorts and Mendelian Randomization. TET2 is associated with an increased risk of overall stroke (OR = 1.06, P = 0.02), ischemic stroke (OR = 1.05, P = 0.03), transient ischemic attack (OR = 1.07, P = 0.01) and small vessel stroke (OR = 1.29, P = 0.01), as well as adverse 90-day modified Rankin scale (mRS ≥ 3) before (OR = 1.34, P = 0.005) and after adjusted for age, sex, and stroke severity (OR = 1.30, P = 0.02). While the presence of any CH mutation is associated with intracerebral hemorrhage (ICH) (OR = 1.21, P = 0.02), specific mutations, SRSF2 and ASXL1 are protective against ICH (OR = 0.9, P = 0.04) and nontraumatic subarachnoid hemorrhage (OR = 0.92, P = 0.03), respectively. In conclusion, the study provided genetic evidence that TET2 is strongly associated with an increased risk of ischemic stroke and poor functional recovery. Future studies clarifying the relationship between CH and hemorrhagic stroke subtypes are needed.
{"title":"Multi-Cohort Analysis Reveals Genetic Predispositions to Clonal Hematopoiesis as Mutation-Specific Risk Factors for Stroke","authors":"Shuyang Lin, Yang E. Li, Yan Wang","doi":"10.1002/ggn2.202400047","DOIUrl":"10.1002/ggn2.202400047","url":null,"abstract":"<p>Recent observational studies have found an association between Clonal Hematopoesis (CH) and strokes but with incomplete results. This study aims to comprehensively characterize mutation-specific effects of CH on ischemic and hemorrhagic stroke subtypes and 90-day functional outcomes through publicly available genome-wide association study (GWAS) cohorts and Mendelian Randomization. TET2 is associated with an increased risk of overall stroke (OR = 1.06, <i>P</i> = 0.02), ischemic stroke (OR = 1.05, <i>P</i> = 0.03), transient ischemic attack (OR = 1.07, <i>P</i> = 0.01) and small vessel stroke (OR = 1.29, <i>P</i> = 0.01), as well as adverse 90-day modified Rankin scale (mRS ≥ 3) before (OR = 1.34, <i>P</i> = 0.005) and after adjusted for age, sex, and stroke severity (OR = 1.30, <i>P</i> = 0.02). While the presence of any CH mutation is associated with intracerebral hemorrhage (ICH) (OR = 1.21, <i>P</i> = 0.02), specific mutations, SRSF2 and ASXL1 are protective against ICH (OR = 0.9, <i>P</i> = 0.04) and nontraumatic subarachnoid hemorrhage (OR = 0.92, <i>P</i> = 0.03), respectively. In conclusion, the study provided genetic evidence that TET2 is strongly associated with an increased risk of ischemic stroke and poor functional recovery. Future studies clarifying the relationship between CH and hemorrhagic stroke subtypes are needed.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ggn2.202400047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Sharing one's evidence has been at the core of what we now call “science” for hundreds of years. Roger Bacon wrote in the 13th century that “theories supplied by reason should be verified by sensory data, aided by instruments, and corroborated by trustworthy witnesses.”<sup>[</sup><span><sup>1</sup></span><sup>]</sup> In the modern age, when all science is aided by computers and rich troves of digital data, is it not entirely normal for us, as trustworthy witnesses, to expect to see these data before we accede to someone else's conclusions? Gregor Mendel's transformative paper on pea genetics from 1866 is full of tables sharing “raw” data; tables which themselves have led to years of healthy statistical debate regarding whether Mendel or his assistants may have artificially cleaned their data to produce more idealized outcomes.<sup>[</sup><span><sup>2</sup></span><sup>]</sup></p><p>In this light, modern data availability debates should not be considered something new, but instead another step in an ongoing movement that aims to build a shared and empirically grounded understanding of our natural world.</p><p>This month, <i>Advanced Genetics</i> is joining other Wiley journals in implementing a “Mandates Data Sharing” policy (Data Sharing Policy | Wiley) (https://authorservices.wiley.com/author-resources/Journal-Authors/open-access/data-sharing-citation/data-sharing-policy.html). We and the other participating journals require that authors openly share data underlying their publications and upgrade our editorial workflows to better support data sharing and optional data peer-review. This initiative covers 88 Wiley Journals by now across various fields, such as cell and molecular biology, genetics, geoscience, microbiology, plant science, physics, computer science, and social science (Table S1, Supporting Information). We also intend to mandate minimum standards for that data, as per an initiative that began in 2023 with a group of Wiley Ecology & Evolution Journals.<sup>[</sup><span><sup>3</sup></span><sup>]</sup> It aligns with the focus on open science and open data sharing from major science funders around the world. The declaration from the White House Office of Science and Technology Policy in 2022, which strengths data sharing requirements for US-funded researchers, is only one example of this growing trend (https://www.whitehouse.gov/ostp/news-updates/2022/08/25/breakthroughs-for-alldelivering-equitable-access-to-americas-research/).</p><p>Open sharing of nucleotide sequence data through the interlinked databases of the International Nucleotide Sequence Database Collaboration (https://www.insdc.org/) has been a standard condition of publication at major genetics journals for over three decades, and many genetics and molecular biology journals require that authors similarly deposit and share other “omics” data-types, for which the community has developed a range of high-quality centralized public repositories such as GenBank (https://
{"title":"Upgrading Data Sharing Policies to Maximize Utility and Impact in Genetics and Genomics Research","authors":"Yuming Hu, Lei Lei, Kerstin Brachhold","doi":"10.1002/ggn2.202400055","DOIUrl":"10.1002/ggn2.202400055","url":null,"abstract":"<p>Sharing one's evidence has been at the core of what we now call “science” for hundreds of years. Roger Bacon wrote in the 13th century that “theories supplied by reason should be verified by sensory data, aided by instruments, and corroborated by trustworthy witnesses.”<sup>[</sup><span><sup>1</sup></span><sup>]</sup> In the modern age, when all science is aided by computers and rich troves of digital data, is it not entirely normal for us, as trustworthy witnesses, to expect to see these data before we accede to someone else's conclusions? Gregor Mendel's transformative paper on pea genetics from 1866 is full of tables sharing “raw” data; tables which themselves have led to years of healthy statistical debate regarding whether Mendel or his assistants may have artificially cleaned their data to produce more idealized outcomes.<sup>[</sup><span><sup>2</sup></span><sup>]</sup></p><p>In this light, modern data availability debates should not be considered something new, but instead another step in an ongoing movement that aims to build a shared and empirically grounded understanding of our natural world.</p><p>This month, <i>Advanced Genetics</i> is joining other Wiley journals in implementing a “Mandates Data Sharing” policy (Data Sharing Policy | Wiley) (https://authorservices.wiley.com/author-resources/Journal-Authors/open-access/data-sharing-citation/data-sharing-policy.html). We and the other participating journals require that authors openly share data underlying their publications and upgrade our editorial workflows to better support data sharing and optional data peer-review. This initiative covers 88 Wiley Journals by now across various fields, such as cell and molecular biology, genetics, geoscience, microbiology, plant science, physics, computer science, and social science (Table S1, Supporting Information). We also intend to mandate minimum standards for that data, as per an initiative that began in 2023 with a group of Wiley Ecology & Evolution Journals.<sup>[</sup><span><sup>3</sup></span><sup>]</sup> It aligns with the focus on open science and open data sharing from major science funders around the world. The declaration from the White House Office of Science and Technology Policy in 2022, which strengths data sharing requirements for US-funded researchers, is only one example of this growing trend (https://www.whitehouse.gov/ostp/news-updates/2022/08/25/breakthroughs-for-alldelivering-equitable-access-to-americas-research/).</p><p>Open sharing of nucleotide sequence data through the interlinked databases of the International Nucleotide Sequence Database Collaboration (https://www.insdc.org/) has been a standard condition of publication at major genetics journals for over three decades, and many genetics and molecular biology journals require that authors similarly deposit and share other “omics” data-types, for which the community has developed a range of high-quality centralized public repositories such as GenBank (https://","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"5 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11672304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria T. Bernardi, Memoona Ramzan, Laura Calderon, Franco Salvatore, Maria Agustina De Rosa, Stephanie Bivona, Romina Armando, Natalia Vazquez, Maria Esnaola Azcoiti, Marcelo A. Marti, Claudia Arberas, Maria Gabriela Ropelato, Silvina Olha, Byron L. Lam, Fred F. Telischi, Mustafa Tekin, Katherina Walz
Hearing loss is the most common sensory defect in humans, affecting normal communication. In most cases, hearing loss is a multifactorial disorder caused by both genetic and environmental factors, but single-gene mutations can lead to syndromic or non-syndromic hearing loss. Monoallelic variants in ACTG1, coding for gamma (γ)-actin, are associated with classical Baraitser-Winter Syndrome type 2 (BRWS2, nonsyndromic deafness, and a variety of clinical presentations not fitting the original BRWS2 description or nonsyndromic deafness. Here two unrelated patients with ACTG1 variants are reported, having severe hearing loss as a common phenotype but with different clinical presentations, supporting the extreme variability of ACTG1-related disorders.
{"title":"Extreme Phenotypic Variability of ACTG1-Related Disorders in Hearing Loss","authors":"Maria T. Bernardi, Memoona Ramzan, Laura Calderon, Franco Salvatore, Maria Agustina De Rosa, Stephanie Bivona, Romina Armando, Natalia Vazquez, Maria Esnaola Azcoiti, Marcelo A. Marti, Claudia Arberas, Maria Gabriela Ropelato, Silvina Olha, Byron L. Lam, Fred F. Telischi, Mustafa Tekin, Katherina Walz","doi":"10.1002/ggn2.202400040","DOIUrl":"10.1002/ggn2.202400040","url":null,"abstract":"<p>Hearing loss is the most common sensory defect in humans, affecting normal communication. In most cases, hearing loss is a multifactorial disorder caused by both genetic and environmental factors, but single-gene mutations can lead to syndromic or non-syndromic hearing loss. Monoallelic variants in <i>ACTG1</i>, coding for gamma (γ)-actin, are associated with classical Baraitser-Winter Syndrome type 2 (BRWS2, nonsyndromic deafness, and a variety of clinical presentations not fitting the original BRWS2 description or nonsyndromic deafness. Here two unrelated patients with <i>ACTG1</i> variants are reported, having severe hearing loss as a common phenotype but with different clinical presentations, supporting the extreme variability of <i>ACTG1</i>-related disorders.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"5 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11672310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The VISTA enhancer database is a valuable resource for evaluating predicted enhancers in humans and mice. In addition to thousands of validated positive regions (VPRs) in the human and mouse genomes, the database also contains similar numbers of validated negative regions (VNRs). It is previously shown that the VPRs are on average half as long as predicted overlapping enhancers that are highly conserved and hypothesize that the VPRs may be truncated forms of long bona fide enhancers. Here, it is shown that like the VPRs, the VNRs also are under strong evolutionary constraints and overlap predicted enhancers in the genomes. The VNRs are also on average half as long as predicted overlapping enhancers that are highly conserved. Moreover, the VNRs and the VPRs display similar cell/tissue-specific modification patterns of key epigenetic marks of active enhancers. Furthermore, the VNRs and the VPRs show similar impact score spectra of in silico mutagenesis. These highly similar properties between the VPRs and the VNRs suggest that like the VPRs, the VNRs may also be truncated forms of long bona fide enhancers.
{"title":"Validated Negative Regions (VNRs) in the VISTA Database might be Truncated Forms of Bona Fide Enhancers","authors":"Pengyu Ni, Siwen Wu, Zhengchang Su","doi":"10.1002/ggn2.202300209","DOIUrl":"10.1002/ggn2.202300209","url":null,"abstract":"<p>The VISTA enhancer database is a valuable resource for evaluating predicted enhancers in humans and mice. In addition to thousands of validated positive regions (VPRs) in the human and mouse genomes, the database also contains similar numbers of validated negative regions (VNRs). It is previously shown that the VPRs are on average half as long as predicted overlapping enhancers that are highly conserved and hypothesize that the VPRs may be truncated forms of long bona fide enhancers. Here, it is shown that like the VPRs, the VNRs also are under strong evolutionary constraints and overlap predicted enhancers in the genomes. The VNRs are also on average half as long as predicted overlapping enhancers that are highly conserved. Moreover, the VNRs and the VPRs display similar cell/tissue-specific modification patterns of key epigenetic marks of active enhancers. Furthermore, the VNRs and the VPRs show similar impact score spectra of in silico mutagenesis. These highly similar properties between the VPRs and the VNRs suggest that like the VPRs, the VNRs may also be truncated forms of long bona fide enhancers.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ggn2.202300209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140971956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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