NPJ Genomic Medicine最新文献

{"title":"Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer.","authors":"Daniel R Barnes, Jonathan P Tyrer, Joe Dennis, Goska Leslie, Manjeet K Bolla, Michael Lush, Amber M Aeilts, Kristiina Aittomäki, Nadine Andrieu, Irene L Andrulis, Hoda Anton-Culver, Adalgeir Arason, Banu K Arun, Judith Balmaña, Elisa V Bandera, Rosa B Barkardottir, Lieke P V Berger, Amy Berrington de Gonzalez, Pascaline Berthet, Katarzyna Białkowska, Line Bjørge, Amie M Blanco, Marinus J Blok, Kristie A Bobolis, Natalia V Bogdanova, James D Brenton, Henriett Butz, Saundra S Buys, Maria A Caligo, Ian Campbell, Carmen Castillo, Kathleen B M Claes, Sarah V Colonna, Linda S Cook, Mary B Daly, Agnieszka Dansonka-Mieszkowska, Miguel de la Hoya, Anna deFazio, Allison DePersia, Yuan Chun Ding, Jennifer A Doherty, Susan M Domchek, Thilo Dörk, Zakaria Einbeigi, Christoph Engel, D Gareth Evans, Lenka Foretova, Renée T Fortner, Florentia Fostira, Maria Cristina Foti, Eitan Friedman, Megan N Frone, Patricia A Ganz, Aleksandra Gentry-Maharaj, Gord Glendon, Andrew K Godwin, Anna González-Neira, Mark H Greene, Jacek Gronwald, Aliana Guerrieri-Gonzaga, Ute Hamann, Thomas V O Hansen, Holly R Harris, Jan Hauke, Florian Heitz, Frans B L Hogervorst, Maartje J Hooning, John L Hopper, Chad D Huff, David G Huntsman, Evgeny N Imyanitov, Louise Izatt, Anna Jakubowska, Paul A James, Ramunas Janavicius, Esther M John, Siddhartha Kar, Beth Y Karlan, Catherine J Kennedy, Lambertus A L M Kiemeney, Irene Konstantopoulou, Jolanta Kupryjanczyk, Yael Laitman, Ofer Lavie, Kate Lawrenson, Jenny Lester, Fabienne Lesueur, Carlos Lopez-Pleguezuelos, Phuong L Mai, Siranoush Manoukian, Taymaa May, Iain A McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Jennifer M Mongiovi, Marco Montagna, Kirsten B Moysich, Susan L Neuhausen, Finn C Nielsen, Catherine Noguès, Edit Oláh, Olufunmilayo I Olopade, Ana Osorio, Laura Papi, Harsh Pathak, Celeste L Pearce, Inge S Pedersen, Ana Peixoto, Tanja Pejovic, Pei-Chen Peng, Beth N Peshkin, Paolo Peterlongo, C Bethan Powell, Darya Prokofyeva, Miquel Angel Pujana, Paolo Radice, Muhammad U Rashid, Gad Rennert, George Richenberg, Dale P Sandler, Naoko Sasamoto, Veronica W Setiawan, Priyanka Sharma, Weiva Sieh, Christian F Singer, Katie Snape, Anna P Sokolenko, Penny Soucy, Melissa C Southey, Dominique Stoppa-Lyonnet, Rebecca Sutphen, Christian Sutter, Yen Y Tan, Manuel R Teixeira, Kathryn L Terry, Liv Cecilie V Thomsen, Marc Tischkowitz, Amanda E Toland, Toon Van Gorp, Ana Vega, Digna R Velez Edwards, Penelope M Webb, Jeffrey N Weitzel, Nicolas Wentzensen, Alice S Whittemore, Stacey J Winham, Anna H Wu, Siddhartha Yadav, Yao Yu, Argyrios Ziogas, Andrew Berchuck, Fergus J Couch, Ellen L Goode, Marc T Goodman, Alvaro N Monteiro, Kenneth Offit, Susan J Ramus, Harvey A Risch, Joellen M Schildkraut, Mads Thomassen, Jacques Simard, Douglas F Easton, Michelle R Jones, Georgia Chenevix-Trench, Simon A Gayther, Antonis C Antoniou, Paul D P Pharoah","doi":"10.1038/s41525-025-00529-w","DOIUrl":"10.1038/s41525-025-00529-w","url":null,"abstract":"<p><p>Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3'-UTR SNP rs78378222-T's association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28-1.62, P = 1.76 × 10^-9). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95% CI:1.37-1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date - demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"73"},"PeriodicalIF":5.3,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12635163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RareLink: scalable REDCap-based framework for rare disease interoperability linking international registries to FHIR and Phenopackets.","authors":"Adam S L Graefe, Filip Rehburg, Samer Alkarkoukly, Daniel Danis, Ana Grönke, Miriam R Hübner, Alexander Bartschke, Thomas Debertshäuser, Sophie A I Klopfenstein, Julian Saß, Julia Fleck, Mirko Rehberg, Jana Zschüntzsch, Elisabeth F Nyoungui, Tatiana Kalashnikova, Luis Murguía-Favela, Beata Derfalvi, Nicola A M Wright, Shahida Moosa, Soichi Ogishima, Oliver Semler, Susanna Wiegand, Peter Kühnen, Christopher J Mungall, Melissa A Haendel, Peter N Robinson, Sylvia Thun, Oya Beyan","doi":"10.1038/s41525-025-00534-z","DOIUrl":"10.1038/s41525-025-00534-z","url":null,"abstract":"<p><p>While Research Electronic Data Capture (REDCap) is widely adopted in rare disease research, its unconstrained data format often lacks native interoperability with global health standards, limiting secondary use. We developed RareLink, an open-source framework implementing our published ontology-based rare disease common data model. It enables standardised data exchange between REDCap, international registries, and downstream analysis tools by linking Global Alliance for Genomics and Health Phenopackets and Health Level 7 Fast Healthcare Interoperability Resources (FHIR) instances conforming to International Patient Summary and Genomics Reporting profiles. RareLink was developed in three phases across Germany, Canada, South Africa, and Japan for registry and data analysis purposes. We defined a simulated Kabuki syndrome cohort and demonstrated data export to Phenopackets and FHIR. RareLink can enhance the clinical utility of REDCap through its global applicability, supporting equitable rare disease research. Broader adoption and coordination with international entities are thus essential to realise its full potential.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"72"},"PeriodicalIF":5.3,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12627670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PHKA1-associated phosphorylase kinase deficiency: a monogenic disorder of exercise intolerance and myalgia.","authors":"Rebecca L Koch, Angie H Fares, Benjamin T Cocanougher, Jamie Lim, Andrea B Haijer-Schreuder, Terry G J Derks, Sarah C Grünert, Reena Sharma, Karra A Jones, Priya S Kishnani","doi":"10.1038/s41525-025-00527-y","DOIUrl":"10.1038/s41525-025-00527-y","url":null,"abstract":"<p><p>Muscle phosphorylase kinase deficiency results from X-linked pathogenic variants in PHKA1, leading to glycogen storage disease (GSD) type IXα1 (also known as GSD IXd). As part of an international collaboration, we describe 14 previously unreported cases (12 males, 2 females; ClinicalTrials.gov NCT04454216, registered 2020-07-01). We compared our cohort to 18 cases previously reported and to an additional 16 cases identified through the National Institutes of Health All of Us Research Program. The clinical presentations highlight the predominance of myopathic symptoms on exertion and emphasize the variability in age of onset. Examination of muscle biopsies revealed glycogen accumulation and an increase in lipid droplets indicative of mitochondrial dysfunction and mitophagy. We encourage clinicians to maintain a high level of suspicion even in the setting of normal blood creatine kinase levels. Comprehensive longitudinal natural history studies remain necessary to improve disease detection, inform management guidelines, and provide a foundation for therapeutic development.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"71"},"PeriodicalIF":5.3,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12603314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145489308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole genome sequencing-based analysis of genetic predisposition to adult glioblastoma.","authors":"Mark P van Opijnen, Devin R van Valkengoed, Joep de Ligt, Filip Y F de Vos, Marike L D Broekman, Edwin Cuppen, Roelof Koster","doi":"10.1038/s41525-025-00526-z","DOIUrl":"10.1038/s41525-025-00526-z","url":null,"abstract":"<p><p>The germline genetic susceptibility to adult glioblastoma remains unclear. With the option of broad molecular testing, it is crucial that clinicians are aware of the a priori probability of finding germline predisposition in glioblastoma patients. Here, we studied the genetic predisposition to adult glioblastoma using paired tumor-normal WGS data in an unselected, average cohort of 92 glioma WHO grade 4 patients. In 10 patients (11%), 12 Pathogenic Germline Variants (PGVs) were found in genes strongly associated with familial glioblastoma (MSH6 (3x), PMS2 (5x), MSH2, NF1, BRCA1) or medulloblastoma (SUFU). In six of these patients (60%), causality was supported by a second (somatic) event and/or a matching genome-wide mutational signature. Thus, germline predisposition does play a role in the development of adult glioblastoma, with mismatch repair deficiency being the main mechanism. Our results also highlight the benefits of tumor-normal WGS for glioblastoma patients and their families, beyond identifying actionable mutations for therapy.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"70"},"PeriodicalIF":4.8,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12575641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of whole genome sequencing for carrier and diagnostic assessment of spinal muscular atrophy in Taiwan.","authors":"Li-Ling Lin, Pei-Miao Chien, Tzu-Hung Hsiao, Han-Yu Ye, Shu-Hsuan Liu, Tsang-Ming Ko, Chien-Hao Huang, Pei-Lung Chen, Wen-Chun Chen, Yuh-Tsyr Chou, Chao-Szu Wu, Hung-Hsin Chen, Yin-Hsiu Chien, Jacob Shu-Jui Hsu","doi":"10.1038/s41525-025-00524-1","DOIUrl":"10.1038/s41525-025-00524-1","url":null,"abstract":"<p><p>This study aimed to evaluate the feasibility of whole-genome sequencing (WGS) combined with computational tools for spinal muscular atrophy (SMA) carrier screening and disease diagnosis in Taiwan. WGS data from 1492 Taiwan Biobank participants and two patients with SMA were analysed to determine the SMN1 and SMN2 copy numbers using Illumina DRAGEN SMN Caller and validated by multiplex ligation-dependent probe amplification (MLPA). Among 1480 samples analysed, 23 SMA carriers were identified, yielding a carrier frequency of 1.55%. MLPA confirmed the accuracy of SMN1 and SMN2 copy number results detected using WGS. Both patients with SMA presented compound heterozygous variants with one SMN1 copy loss and the other SMN1 variant, specifically SMN1,c.815A>G, and SMN1,c.81+2_81+3delTG, respectively. Taken together, combining WGS with advanced bioinformatics tools is a feasible and promising approach for SMA carrier screening and disease diagnosis.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"69"},"PeriodicalIF":4.8,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12572182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145401395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of SPECC1L translation initiation by intragenic deletion: novel pathogenic mechanism in Teebi-hypertelorism syndrome.","authors":"Arwa Babai, Daniela Oliveira, Andriana Gialeli, Malgorzata Drozniewska, Yaroslav Kainov, Cristina Dias","doi":"10.1038/s41525-025-00513-4","DOIUrl":"10.1038/s41525-025-00513-4","url":null,"abstract":"<p><p>Missense and loss-of-function variants in SPECC1L are associated with Teebi Hypertelorism Syndrome 1 (TBHS1). Here, we report a novel SPECC1L intragenic deletion encompassing exon 3, which contains the canonical translation start site, in two related individuals with craniofacial features consistent with TBHS1. We use functional overexpression assays to demonstrate that this deletion leads to alternative start codon usage and protein truncation. This is the first report of a SPECC1L intragenic deletion associated with TBHS1. Our findings suggest that deletion of the canonical N-terminal disordered region of SPECC1L contributes to craniofacial anomalies, warranting further investigation into its role in neural crest development.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"68"},"PeriodicalIF":4.8,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12541090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A ciliopathy combining Joubert syndrome and Oro-Facial-Digital syndrome caused by bi-allelic 5'-UTR loss-of-function CEP83 variant.","authors":"Matan M Jean, Anan Yunis, Tzofit Elbaz-Biton, Vadim Dolgin, Ginat Narkis, Analia Michaelovsky, Marina Eskin-Schwartz, Alexandra A Tsitrina, Nadav Agam, Tomer Poleg, Amit Safran, Ofek Freund, Noam Hadar, Dan Levy, Ilan Shelef, Khalil El Amour, Hagit Flusser, Ohad S Birk","doi":"10.1038/s41525-025-00514-3","DOIUrl":"10.1038/s41525-025-00514-3","url":null,"abstract":"<p><p>Oro-Facial-Digital Syndrome (OFDS) and Joubert syndrome are ciliary disorders. Fifteen individuals of consanguineous Bedouin kindred presented with global developmental delay with no speech, and a clear OFDS phenotype, combined with Joubert syndrome, with MRI showing hypoplastic corpus callosum and molar tooth sign. Renal and liver function tests and ultrasound were unremarkable. Within a 0.5 Mb disease-associated locus (LOD score 6.2), whole genome sequencing identified a single variant: CEP83 NG_051825.2:g.5774dupG, (NM_016122.3):c.-278dupG. Patient fibroblasts showed aberrantly long cilia, and alternative splicing of CEP83 5'UTR, skipping most of exon 1 of the canonical transcript, and frameshift, abrogating CEP83 mRNA and protein expression. CEP83 acts in primary cilium assembly. CEP83 biallelic missense or in-frame deletions, with presumed residual function, were previously associated with early-onset nephronophthisis culminating in end-stage renal disease. We now demonstrate that a biallelic complete loss-of-function CEP83 variant culminates in elongated primary cilia, causing OFDS with Joubert-like features without evident renal involvement.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"66"},"PeriodicalIF":5.3,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12514222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole genome sequencing in adolescent idiopathic scoliosis cohort implicates multiple biological pathways.","authors":"Islam Oguz Tuncay, Eun Kyoung Lee, Anxhela Gustafson, Yoonsuh Lee, Dawoon Jung, June-Young Koh, Wonchul Lee, Sangmoon Lee, Kamran Shazand","doi":"10.1038/s41525-025-00520-5","DOIUrl":"10.1038/s41525-025-00520-5","url":null,"abstract":"<p><p>Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder. This study used whole-genome sequencing (WGS) to investigate the genetic basis of AIS in 119 patients from 103 families. Our WGS analysis identified known pathogenic or protein-truncating variants in 15 probands, and other strong or moderate candidate variants in 69 additional patients. We found both coding and non-coding mutations, including structural variants. Candidate genes included known AIS genes (e.g., COL11A2, FBN1) and genes linked to other musculoskeletal disorders with scoliosis (e.g., RYR1). Association analysis confirmed four known AIS single-nucleotide polymorphisms in our cohort. Gene set enrichment analysis revealed four gene clusters related to skeletal muscle contraction, extracellular matrix, and gene expression regulation. This WGS-based approach identified clinically relevant genetic variations and biological pathways in AIS patients, offering valuable insights into its complex development.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"67"},"PeriodicalIF":4.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12514243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meta-analysis reveals transcription factors and DNA binding domain variants associated with congenital heart defect and orofacial cleft.","authors":"Raehoon Jeong, Martha L Bulyk","doi":"10.1038/s41525-025-00525-0","DOIUrl":"10.1038/s41525-025-00525-0","url":null,"abstract":"<p><p>Many congenital anomaly patients lack genetic diagnoses because there are many disease genes as yet to be discovered. We applied a gene burden test incorporating de novo predicted-loss-of-function (pLoF) and likely damaging missense variants together with inherited pLoF variants to a collection of congenital heart defect (CHD) and orofacial cleft (OFC) parent-offspring trio cohorts (n = 3835 and 1844, respectively). We identified 17 novel candidate CHD genes and 8 novel candidate OFC genes, of which many were known developmental disorder genes. TFs were enriched among the significant genes; 14 and 8 transcription factor (TF) genes showed significant variant burden for CHD and OFC, respectively. In total, 30 affected children had a de novo missense variant in a DNA binding domain of a known CHD, OFC, and other developmental disorder TF genes. Our results suggest candidate pathogenic variants in CHD and OFC and their potentially pleiotropic effects in other developmental disorders.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"63"},"PeriodicalIF":4.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic analyses across cardiovascular traits: leveraging genetic correlations to empower locus discovery and prediction in common cardiovascular diseases.","authors":"Paloma Jordà, Yiwei Lai, Amélie Jeuken, Louis-Philippe Lemieux Perreault, Elisabeth Goulet, Najim Lahrouchi, Anna Nozza, Michael W Tanck, Peter Guerra, Julia Cadrin-Tourigny, Simon de Denus, Connie R Bezzina, Guillaume Lettre, David Busseuil, Marie-Pierre Dubé, Jean-Claude Tardif, Rafik Tadros","doi":"10.1038/s41525-025-00515-2","DOIUrl":"10.1038/s41525-025-00515-2","url":null,"abstract":"<p><p>Common genetic variation detected by genome-wide association studies (GWAS) partially explains variability in the spectrum of cardiac phenotypes. In this work, we explore genetic correlations among 58 cardiac-related traits/diseases, detecting novel ones. We subsequently employ multi-trait analysis of GWAS (MTAG), which meta-analyzes genetically correlated traits, to improve genomic loci discovery and prediction in atrial fibrillation (AF), coronary artery disease (CAD), and heart failure (HF). We identify 19 novel loci specific for AF, 131 for CAD, and 141 for HF. Polygenic scores (PGS) in 15,177 Canadian individuals show similar results when PGS are derived from conventional GWAS versus MTAG summary statistics, although MTAG-PGS improve prediction and discrimination of CAD in females [∆R² 1.735% (95% Confidence Interval (CI): 0.609-2.856); Net reclassification index 0.208 (95%CI: 0.139-0.277)]. This work describes new relevant genetic correlations among cardiac-related traits/diseases and supports MTAG to improve loci discovery in common cardiovascular diseases and potentially improve the prediction of CAD in females.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"65"},"PeriodicalIF":4.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12480102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}