Thomas J Dinneen, Fiana Ní Ghrálaigh, Cathal Ormond, Elizabeth A Heron, George Kirov, Lorna M Lopez, Louise Gallagher
{"title":"Polygenic scores stratify neurodevelopmental copy number variant carrier cognitive outcomes in the UK Biobank.","authors":"Thomas J Dinneen, Fiana Ní Ghrálaigh, Cathal Ormond, Elizabeth A Heron, George Kirov, Lorna M Lopez, Louise Gallagher","doi":"10.1038/s41525-024-00426-8","DOIUrl":"https://doi.org/10.1038/s41525-024-00426-8","url":null,"abstract":"<p><p>Rare copy-number variants associated with neurodevelopmental conditions (ND-CNVs) exhibit variable expressivity of clinical, physical, behavioural outcomes. Findings from clinically ascertained cohorts suggest this variability may be partly due to additional genetic variation. Here, we assessed the impact of polygenic scores (PGS) and rare variants on ND-CNV carrier fluid intelligence (FI) scores in the UK Biobank. Greater PGS for cognition (PS<sub>Cog</sub>) and educational attainment (PS<sub>EA</sub>) is associated with increased FI scores in all ND-CNVs (n = 1317), 15q11.2 del. (n = 543), and 16p13.11 dup. carriers (n = 275). No association of rare variants associated with intellectual disability, autism, or putatively loss-of-function, brain-expressed genes was found. Positive predictive values in the first deciles of PS<sub>cog</sub> and PS<sub>EA</sub> showed a two- to five-fold increase in the rate of low FI scores compared to baseline rates. These findings demonstrate that PGS can stratify ND-CNV carrier cognitive outcomes in a population-based cohort.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"43"},"PeriodicalIF":4.7,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350890","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}
Karim H Saba, Valeria Difilippo, Emelie Styring, Jenny Nilsson, Linda Magnusson, Hilda van den Bos, René Wardenaar, Diana C J Spierings, Floris Foijer, Michaela Nathrath, Felix Haglund de Flon, Daniel Baumhoer, Karolin H Nord
{"title":"CDK4 is co-amplified with either TP53 promoter gene fusions or MDM2 through distinct mechanisms in osteosarcoma.","authors":"Karim H Saba, Valeria Difilippo, Emelie Styring, Jenny Nilsson, Linda Magnusson, Hilda van den Bos, René Wardenaar, Diana C J Spierings, Floris Foijer, Michaela Nathrath, Felix Haglund de Flon, Daniel Baumhoer, Karolin H Nord","doi":"10.1038/s41525-024-00430-y","DOIUrl":"https://doi.org/10.1038/s41525-024-00430-y","url":null,"abstract":"<p><p>Amplification of the MDM2 and CDK4 genes on chromosome 12 is commonly associated with low-grade osteosarcomas. In this study, we conducted high-resolution genomic and transcriptomic analyses on 33 samples from 25 osteosarcomas, encompassing both high- and low-grade cases with MDM2 and/or CDK4 amplification. We discerned four major subgroups, ranging from nearly intact genomes to heavily rearranged ones, each harbouring CDK4 and MDM2 amplification or CDK4 amplification with TP53 structural alterations. While amplicons involving MDM2 exhibited signs of an initial chromothripsis event, no evidence of chromothripsis was found in TP53-rearranged cases. Instead, the initial disruption of the TP53 locus led to co-amplification of the CDK4 locus. Additionally, we observed recurring promoter swapping events involving the regulatory regions of the FRS2, PLEKHA5, and TP53 genes. These events resulted in ectopic expression of partner genes, with the ELF1 gene being upregulated by the FRS2 and TP53 promoter regions in two distinct cases.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"42"},"PeriodicalIF":4.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350971","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}
Laurence Pacot, Dominique Vidaud, Manuela Ye, Albain Chansavang, Audrey Coustier, Theodora Maillard, Cécile Barbance, Ingrid Laurendeau, Bérénice Hébrard, Ariane Lunati-Rozie, Benoît Funalot, Pierre Wolkenstein, Michel Vidaud, Alice Goldenberg, Fanny Morice-Picard, Djihad Hadjadj, Béatrice Parfait, Eric Pasmant
{"title":"Prenatal diagnosis for neurofibromatosis type 1 and the pitfalls of germline mosaics.","authors":"Laurence Pacot, Dominique Vidaud, Manuela Ye, Albain Chansavang, Audrey Coustier, Theodora Maillard, Cécile Barbance, Ingrid Laurendeau, Bérénice Hébrard, Ariane Lunati-Rozie, Benoît Funalot, Pierre Wolkenstein, Michel Vidaud, Alice Goldenberg, Fanny Morice-Picard, Djihad Hadjadj, Béatrice Parfait, Eric Pasmant","doi":"10.1038/s41525-024-00425-9","DOIUrl":"10.1038/s41525-024-00425-9","url":null,"abstract":"<p><p>We report our 5-year experience in neurofibromatosis type 1 prenatal diagnosis (PND): 205 PNDs in 146 women (chorionic villus biopsies, 88% or amniocentesis, 12%). The NF1 variant was present in 85 (41%) and absent in 122 (59%) fetuses. Among 205 pregnancies (207 fetuses), 135 were carried to term (119 unaffected and 16 NF1 affected children), 69 pregnancy terminations (affected fetuses), 2 miscarriages, and 1 in utero death. The majority of PND requests came from parents with sporadic NF1. We describe two PNDs in women with mosaic NF1. In both families, direct PND showed the absence of the maternal NF1 variant in the fetus. However, microsatellite markers analysis showed that the risk haplotype had been transmitted. These rare cases of germline mosaicism illustrate the pitfall of indirect PND. Our study illustrates the crucial consequences of PND for medical and genetic counseling decisions. We also point to the challenges of germline mosaics.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"41"},"PeriodicalIF":4.7,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11381512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154698","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}
Ivan Ellson, Jordi Martorell-Marugán, Pedro Carmona-Sáez, Verónica Ramos-Mejia
{"title":"MiRNA expression as outcome predictor in pediatric AML: systematic evaluation of a new model.","authors":"Ivan Ellson, Jordi Martorell-Marugán, Pedro Carmona-Sáez, Verónica Ramos-Mejia","doi":"10.1038/s41525-024-00424-w","DOIUrl":"10.1038/s41525-024-00424-w","url":null,"abstract":"<p><p>Accurately predicting patient outcomes is essential for optimizing treatment and improving outcomes in pediatric acute myeloid leukemia (AML). In recent years, microRNAs have emerged as a promising prognostic marker, with a growing body of evidence supporting their potential predictive value. We systematically reviewed all previous studies that have analyzed the expression of microRNAs as predictors of survival in pediatric AML and found 16 microRNAs and 4 microRNA signatures previously proposed as predictors of survival. We then used a public access cohort of 1414 pediatric AML patients from the TARGET project to develop a new predictive model using penalized lasso Cox regression based on microRNA expression. Here we propose a new score based on a 37-microRNA signature that is associated with AML and is able to predict survival more accurately than previous microRNA-based methods.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"40"},"PeriodicalIF":4.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897876","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}
W K Jacky Lam, Wanxia Gai, Jinyue Bai, Tommy H C Tam, Wai Fung Cheung, Lu Ji, Irene O L Tse, Amy F C Tsang, Maggie Z J Li, Peiyong Jiang, Man Fai Law, Raymond S M Wong, K C Allen Chan, Y M Dennis Lo
{"title":"Differential detection of megakaryocytic and erythroid DNA in plasma in hematological disorders.","authors":"W K Jacky Lam, Wanxia Gai, Jinyue Bai, Tommy H C Tam, Wai Fung Cheung, Lu Ji, Irene O L Tse, Amy F C Tsang, Maggie Z J Li, Peiyong Jiang, Man Fai Law, Raymond S M Wong, K C Allen Chan, Y M Dennis Lo","doi":"10.1038/s41525-024-00423-x","DOIUrl":"10.1038/s41525-024-00423-x","url":null,"abstract":"<p><p>The tissues of origin of plasma DNA can be revealed by methylation patterns. However, the relative DNA contributions from megakaryocytes and erythroblasts into plasma appeared inconsistent among studies. To shed light into this phenomenon, we developed droplet digital PCR (ddPCR) assays for the differential detection of contributions from these cell types in plasma based on megakaryocyte-specific and erythroblast-specific methylation markers. Megakaryocytic DNA and erythroid DNA contributed a median of 44.2% and 6.2% in healthy individuals, respectively. Patients with idiopathic thrombocytopenic purpura had a significantly higher proportion of megakaryocytic DNA in plasma compared to healthy controls (median: 59.9% versus 44.2%; P = 0.03). Similarly, patients with β-thalassemia were shown to have higher proportions of plasma erythroid DNA compared to healthy controls (median: 50.9% versus 6.2%) (P < 0.0001). Hence, the concurrent analysis of megakaryocytic and erythroid lineage-specific markers could facilitate the dissection of their relative contributions and provide information on patients with hematological disorders.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"39"},"PeriodicalIF":4.7,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893932","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}
Olivia Castellini-Pérez, Elena Povedano, Guillermo Barturen, Manuel Martínez-Bueno, Andrii Iakovliev, Martin Kerick, Raúl López-Domínguez, Concepción Marañón, Javier Martín, Esteban Ballestar, María Orietta Borghi, Weiliang Qiu, Cheng Zhu, Srinivas Shankara, Athina Spiliopoulou, Emanuele de Rinaldis, Elena Carnero-Montoro, Marta E Alarcón-Riquelme
{"title":"Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants.","authors":"Olivia Castellini-Pérez, Elena Povedano, Guillermo Barturen, Manuel Martínez-Bueno, Andrii Iakovliev, Martin Kerick, Raúl López-Domínguez, Concepción Marañón, Javier Martín, Esteban Ballestar, María Orietta Borghi, Weiliang Qiu, Cheng Zhu, Srinivas Shankara, Athina Spiliopoulou, Emanuele de Rinaldis, Elena Carnero-Montoro, Marta E Alarcón-Riquelme","doi":"10.1038/s41525-024-00420-0","DOIUrl":"10.1038/s41525-024-00420-0","url":null,"abstract":"<p><p>The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls. Methylation quantitative trait loci analyses, cytokine and transcription factor activity - epigenetic associations and methylation-expression correlations were conducted. New drug targets were searched for based on differentially methylated genes. In a stratified approach, a total of 974 differential methylation CpG sites with dependency on molecular subtypes and autoantibody profiles were found. Mediation analyses suggested that SLE-associated SNPs in the HLA region exert their risk through DNA methylation changes. Novel genetic variants regulating DNAm in disease or in specific molecular contexts were identified. The epigenetic landscapes showed strong association with transcription factor activity and cytokine levels, conditioned by the molecular context. Epigenetic signals were enriched in known and novel drug targets for SLE. This study reveals possible genetic drivers and consequences of epigenetic variability on SLE heterogeneity and disentangles the DNAm mediation role on SLE genetic risk and novel disease-specific meQTLs. Finally, novel targets for drug development were discovered.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"38"},"PeriodicalIF":4.7,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11252280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141627172","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}
Elizabeth Emma Palmer, Helene Cederroth, Mikk Cederroth, Angelica Maria Delgado-Vega, Natalie Roberts, Fulya Taylan, Ann Nordgren, Lorenzo D Botto
{"title":"Equity in action: The Diagnostic Working Group of The Undiagnosed Diseases Network International.","authors":"Elizabeth Emma Palmer, Helene Cederroth, Mikk Cederroth, Angelica Maria Delgado-Vega, Natalie Roberts, Fulya Taylan, Ann Nordgren, Lorenzo D Botto","doi":"10.1038/s41525-024-00422-y","DOIUrl":"10.1038/s41525-024-00422-y","url":null,"abstract":"<p><p>Rare diseases are recognized as a global public health priority. A timely and accurate diagnosis is a critical enabler for precise and personalized health care. However, barriers to rare disease diagnoses are especially steep for those from historically underserved communities, including low- and middle-income countries. The Undiagnosed Diseases Network International (UDNI) was launched in 2015 to help fill the knowledge gaps that impede diagnosis for rare diseases, and to foster the translation of research into medical practice, aided by active patient involvement. To better pursue these goals, in 2021 the UDNI established the Diagnostic Working Group of the UDNI (UDNI DWG) as a community of practice that would (a) accelerate diagnoses for more families; (b) support and share knowledge and skills by developing Undiagnosed Diseases Programs, particularly those in lower resource areas; and (c) promote discovery and expand global medical knowledge. This Perspectives article documents the initial establishment and iterative co-design of the UDNI DWG.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"37"},"PeriodicalIF":4.7,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11224220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534929","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}
Niccolò Rossi, Najeeb Syed, Alessia Visconti, Elbay Aliyev, Sarah Berry, Mafalda Bourbon, Tim D Spector, Pirro G Hysi, Khalid A Fakhro, Mario Falchi
{"title":"Rare variants at KCNJ2 are associated with LDL-cholesterol levels in a cross-population study.","authors":"Niccolò Rossi, Najeeb Syed, Alessia Visconti, Elbay Aliyev, Sarah Berry, Mafalda Bourbon, Tim D Spector, Pirro G Hysi, Khalid A Fakhro, Mario Falchi","doi":"10.1038/s41525-024-00417-9","DOIUrl":"https://doi.org/10.1038/s41525-024-00417-9","url":null,"abstract":"<p><p>Leveraging whole genome sequencing data of 1751 individuals from the UK and 2587 Qatari subjects, we suggest here an association of rare variants mapping to the sour taste-associated gene KCNJ2 with reduced low-density lipoprotein cholesterol (LDL-C, P = 2.10 × 10<sup>-12</sup>) and with a 22% decreased dietary trans-fat intake. This study identifies a novel candidate rare locus for LDL-C, adding insights into the genetic architecture of a complex trait implicated in cardiovascular disease.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"36"},"PeriodicalIF":4.7,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469662","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}
Anne Van Arsdale, Lauren Turker, Yoke-Chen Chang, Joshua Gould, Bryan Harmon, Elaine C Maggi, Olga Meshcheryakova, Maxwell P Brown, Dana Luong, Koenraad Van Doorslaer, Mark H Einstein, Dennis Y S Kuo, Deyou Zheng, Brian J Haas, Jack Lenz, Cristina Montagna
{"title":"Structure and transcription of integrated HPV DNA in vulvar carcinomas.","authors":"Anne Van Arsdale, Lauren Turker, Yoke-Chen Chang, Joshua Gould, Bryan Harmon, Elaine C Maggi, Olga Meshcheryakova, Maxwell P Brown, Dana Luong, Koenraad Van Doorslaer, Mark H Einstein, Dennis Y S Kuo, Deyou Zheng, Brian J Haas, Jack Lenz, Cristina Montagna","doi":"10.1038/s41525-024-00418-8","DOIUrl":"10.1038/s41525-024-00418-8","url":null,"abstract":"<p><p>HPV infections are associated with a fraction of vulvar cancers. Through hybridization capture and DNA sequencing, HPV DNA was detected in five of thirteen vulvar cancers. HPV16 DNA was integrated into human DNA in three of the five. The insertions were in introns of human NCKAP1, C5orf67, and LRP1B. Integrations in NCKAP1 and C5orf67 were flanked by short direct repeats in the human DNA, consistent with HPV DNA insertions at sites of abortive, staggered, endonucleolytic incisions. The insertion in C5orf67 was present as a 36 kbp, human-HPV-hetero-catemeric DNA as either an extrachromosomal circle or a tandem repeat within the human genome. The human circularization/repeat junction was defined at single nucleotide resolution. The integrated viral DNA segments all retained an intact upstream regulatory region and the adjacent viral E6 and E7 oncogenes. RNA sequencing revealed that the only HPV genes consistently transcribed from the integrated viral DNAs were E7 and E6*I. The other two HPV DNA+ tumors had coinfections, but no evidence for integration. HPV-positive and HPV-negative vulvar cancers exhibited contrasting human, global gene expression patterns partially overlapping with previously observed differences between HPV-positive and HPV-negative cervical and oropharyngeal cancers. A substantial fraction of the differentially expressed genes involved immune system function. Thus, transcription and HPV DNA integration in vulvar cancers resemble those in other HPV-positive cancers. This study emphasizes the power of hybridization capture coupled with DNA and RNA sequencing to identify a broad spectrum of HPV types, determine human genome integration status of viral DNAs, and elucidate their structures.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"35"},"PeriodicalIF":4.7,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11187145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141427333","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}
Sadeep Shrestha, Howard W Wiener, Sabrina Chowdhury, Hidemi Kajimoto, Vinodh Srinivasasainagendra, Olga A Mamaeva, Ujval N Brahmbhatt, Dolena Ledee, Yung R Lau, Luz A Padilla, Jake Y Chen, Nagib Dahdah, Hemant K Tiwari, Michael A Portman
{"title":"Pharmacogenomics of coronary artery response to intravenous gamma globulin in kawasaki disease.","authors":"Sadeep Shrestha, Howard W Wiener, Sabrina Chowdhury, Hidemi Kajimoto, Vinodh Srinivasasainagendra, Olga A Mamaeva, Ujval N Brahmbhatt, Dolena Ledee, Yung R Lau, Luz A Padilla, Jake Y Chen, Nagib Dahdah, Hemant K Tiwari, Michael A Portman","doi":"10.1038/s41525-024-00419-7","DOIUrl":"10.1038/s41525-024-00419-7","url":null,"abstract":"<p><p>Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The mechanism of coronary artery aneurysms (CAA) in KD despite intravenous gamma globulin (IVIG) treatment is not known. We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z ≥ 2.5 and large coronary aneurysm (CAA/L) (N = 92) as z ≥ 5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p < 6.32E-08 most significant). Variants in SMAT4, LOC100127, PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. Functional mapping and annotation (FUMA) analysis identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an area under the receiver operating characteristic curve (AUC) of 0.86. This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD and shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"34"},"PeriodicalIF":5.3,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180307","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}
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