Chen Li, Nicolas De Jay, Shan-Shan Zhang, Xin Fang, Supriya Sharma, Katrina A. Catalano, Venkatesh Sridharan, Zhaoqing Wang, Lei Zhao, Joseph D. Szustakowski, Ching-Pin Chang, Joseph C. Maranville, Emily R. Holzinger, Erika M. Kvikstad
{"title":"Proteome-Wide Mendelian Randomization Identifies Candidate Causal Proteins for Cardiovascular Diseases","authors":"Chen Li, Nicolas De Jay, Shan-Shan Zhang, Xin Fang, Supriya Sharma, Katrina A. Catalano, Venkatesh Sridharan, Zhaoqing Wang, Lei Zhao, Joseph D. Szustakowski, Ching-Pin Chang, Joseph C. Maranville, Emily R. Holzinger, Erika M. Kvikstad","doi":"10.1002/ggn2.202500003","DOIUrl":"10.1002/ggn2.202500003","url":null,"abstract":"<p>Integration of human genomics and other omics across different ancestries provides novel, affordable, and systematic approach for target identification. We used Mendelian randomization approaches to unravel causal associations between 2,940 circulating proteins and 19 CVD. We found 218 proteins that impacted risk of one or more CVDs through forward MR (106 and 182 using cis-pQTLs only and cis- + trans-pQTLs, respectively), among which 107 were previously reported as associated with CVD or CVD-related traits. There were 102 proteins replicated (FDR < 5%, 53 with cis-pQTLs only and 88 with cis- + trans-pQTLs) using the FinnGen Olink data. BTN3A2 was highlighted as a novel candidate gene for ischemic stroke, suggesting a crosstalk between immune modulation and stroke pathogenesis. Single cell integration prioritized PAM for stable angina pectoris and ventricular arrhythmia and LPL for peripheral artery disease, whose transcriptional expressions were enriched in cardiomyocytes. Forward and reverse MR found largely non-overlapping proteins (only 2 overlapped: LGALS4 and MMP12), suggesting distinct proteomic causes and consequences of CVD. Our study provides human genetics-based evidence of novel candidate genes, a foundational step towards full-scale causal human biology-based drug discovery for CVD.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"6 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ggn2.202500003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598403","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}
{"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}
{"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}
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