HGG Advances最新文献

{"title":"Epileptic encephalopathy linked to a DALRD3 missense variant that impairs tRNA modification.","authors":"Kejia Zhang, Katharina Löhner, Henny H Lemmink, Maartje Boon, Jenna M Lentini, Naduni de Silva, Dragony Fu","doi":"10.1016/j.xhgg.2024.100377","DOIUrl":"10.1016/j.xhgg.2024.100377","url":null,"abstract":"<p><p>Epileptic encephalopathies are severe epilepsy syndromes characterized by early onset and progressive cerebral dysfunction. A nonsense variant in the DALR anticodon binding domain containing 3 (DALRD3) gene has been implicated in epileptic encephalopathy, but no other disease-associated variants in DALRD3 have been described. In human cells, the DALRD3 protein forms a complex with the METTL2 methyltransferase to generate the 3-methylcytosine (m3C) modification in specific arginine tRNAs. Here, we identify an individual with a homozygous missense variant in DALRD3 who displays developmental delay, cognitive deficiencies, and multifocal epilepsy. The missense variant substitutes an arginine residue to cysteine (R517C) within the DALR domain of the DALRD3 protein that is required for binding tRNAs. Cells derived from the individual homozygous for the DALRD3-R517C variant exhibit reduced levels of m3C modification in arginine tRNAs, indicating that the R517C variant impairs DALRD3 function. Notably, the DALRD3-R517C protein displays reduced association with METTL2 and loss of interaction with substrate tRNAs. Our results uncover another loss-of-function variant in DALRD3 linked to epileptic encephalopathy disorders. Importantly, these findings underscore DALRD3-dependent tRNA modification as a key contributor to proper brain development and function.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100377"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558996","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":"Proteome-wide association studies for blood lipids and comparison with transcriptome-wide association studies.","authors":"Daiwei Zhang, Boran Gao, Qidi Feng, Ani Manichaikul, Gina M Peloso, Russell P Tracy, Peter Durda, Kent D Taylor, Yongmei Liu, W Craig Johnson, Stacey Gabriel, Namrata Gupta, Joshua D Smith, Francois Aguet, Kristin G Ardlie, Thomas W Blackwell, Robert E Gerszten, Stephen S Rich, Jerome I Rotter, Laura J Scott, Xiang Zhou, Seunggeun Lee","doi":"10.1016/j.xhgg.2024.100383","DOIUrl":"10.1016/j.xhgg.2024.100383","url":null,"abstract":"<p><p>Blood lipid traits are treatable and heritable risk factors for heart disease, a leading cause of mortality worldwide. Although genome-wide association studies (GWASs) have discovered hundreds of variants associated with lipids in humans, most of the causal mechanisms of lipids remain unknown. To better understand the biological processes underlying lipid metabolism, we investigated the associations of plasma protein levels with total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol in blood. We trained protein prediction models based on samples in the Multi-Ethnic Study of Atherosclerosis (MESA) and applied them to conduct proteome-wide association studies (PWASs) for lipids using the Global Lipids Genetics Consortium (GLGC) data. Of the 749 proteins tested, 42 were significantly associated with at least one lipid trait. Furthermore, we performed transcriptome-wide association studies (TWASs) for lipids using 9,714 gene expression prediction models trained on samples from peripheral blood mononuclear cells (PBMCs) in MESA and 49 tissues in the Genotype-Tissue Expression (GTEx) project. We found that although PWASs and TWASs can show different directions of associations in an individual gene, 40 out of 49 tissues showed a positive correlation between PWAS and TWAS signed p values across all the genes, which suggests high-level consistency between proteome-lipid associations and transcriptome-lipid associations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100383"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629679","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":"A corpus of GA4GH phenopackets: Case-level phenotyping for genomic diagnostics and discovery.","authors":"Daniel Danis, Michael J Bamshad, Yasemin Bridges, Andrés Caballero-Oteyza, Pilar Cacheiro, Leigh C Carmody, Leonardo Chimirri, Jessica X Chong, Ben Coleman, Raymond Dalgleish, Peter J Freeman, Adam S L Graefe, Tudor Groza, Peter Hansen, Julius O B Jacobsen, Adam Klocperk, Maaike Kusters, Markus S Ladewig, Allison J Marcello, Teresa Mattina, Christopher J Mungall, Monica C Munoz-Torres, Justin T Reese, Filip Rehburg, Bárbara C S Reis, Catharina Schuetz, Damian Smedley, Timmy Strauss, Jagadish Chandrabose Sundaramurthi, Sylvia Thun, Kyran Wissink, John F Wagstaff, David Zocche, Melissa A Haendel, Peter N Robinson","doi":"10.1016/j.xhgg.2024.100371","DOIUrl":"10.1016/j.xhgg.2024.100371","url":null,"abstract":"<p><p>The Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema was released in 2022 and approved by ISO as a standard for sharing clinical and genomic information about an individual, including phenotypic descriptions, numerical measurements, genetic information, diagnoses, and treatments. A phenopacket can be used as an input file for software that supports phenotype-driven genomic diagnostics and for algorithms that facilitate patient classification and stratification for identifying new diseases and treatments. There has been a great need for a collection of phenopackets to test software pipelines and algorithms. Here, we present Phenopacket Store. Phenopacket Store v.0.1.19 includes 6,668 phenopackets representing 475 Mendelian and chromosomal diseases associated with 423 genes and 3,834 unique pathogenic alleles curated from 959 different publications. This represents the first large-scale collection of case-level, standardized phenotypic information derived from case reports in the literature with detailed descriptions of the clinical data and will be useful for many purposes, including the development and testing of software for prioritizing genes and diseases in diagnostic genomics, machine learning analysis of clinical phenotype data, patient stratification, and genotype-phenotype correlations. This corpus also provides best-practice examples for curating literature-derived data using the GA4GH Phenopacket Schema.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100371"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476454","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":"Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma.","authors":"Li Yan, Qianchuan He, Shiv P Verma, Xu Zhang, Ann-Sophie Giel, Carlo Maj, Kathryn Graz, Elnaz Naderi, Jianhong Chen, Mourad Wagdy Ali, Puya Gharahkhani, Xiang Shu, Kenneth Offit, Pari M Shah, Hans Gerdes, Daniela Molena, Amitabh Srivastava, Stuart MacGregor, Claire Palles, René Thieme, Michael Vieth, Ines Gockel, Thomas L Vaughan, Johannes Schumacher, Matthew F Buas","doi":"10.1016/j.xhgg.2025.100399","DOIUrl":"10.1016/j.xhgg.2025.100399","url":null,"abstract":"<p><p>Inherited genetics represents an important contributor to risk of esophageal adenocarcinoma (EAC), and its precursor Barrett's esophagus (BE). Genome-wide association studies have identified ∼30 susceptibility variants for BE/EAC, yet genetic interactions remain unexamined. To address challenges in large-scale G×G scans, we combined knowledge-guided filtering and machine learning approaches, focusing on genes with (1) known/plausible links to BE/EAC pathogenesis (n = 493) or (2) prior evidence of biological interactions (n = 4,196). Approximately 75 × 10⁶ SNP×SNP interactions were screened via hierarchical group lasso (glinternet) using BEACON GWAS data. The top ∼2,000 interactions retained in each scan were prioritized using p values from single logistic models. Identical scans were repeated among males only (78%), with two independent GWAS datasets used for replication. In overall and male-specific primary replications, 11 of 187 and 20 of 191 interactions satisfied p < 0.05, respectively. The strongest evidence for secondary replication was for rs17744726×rs3217992 among males, with consistent directionality across all cohorts (P_meta = 2.19 × 10^-8); rs3217992 \"T\" was associated with reduced risk only in individuals homozygous for rs17744726 \"G.\" Rs3217992 maps to the CDKN2B 3' UTR and reportedly disrupts microRNA-mediated repression. Rs17744726 maps to an intronic enhancer region in BLK. Through in silico prioritization and experimental validation, we identified a nearby proxy variant (rs4841556) as a functional modulator of enhancer activity. Enhancer-gene mapping and eQTLs implicated BLK and FAM167A as targets. The first systematic G×G investigation in BE/EAC, this study uncovers differential risk associations for CDKN2B variation by BLK genotype, suggesting novel biological dependency between two risk loci encoding key mediators of tumor suppression and inflammation.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100399"},"PeriodicalIF":3.3,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928296","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":"Mapping dynamic regulation of gene expression using single-cell transcriptomics and application to complex disease genetics.","authors":"Hanna Abe, Phillip Lin, Dan Zhou, Douglas M Ruderfer, Eric R Gamazon","doi":"10.1016/j.xhgg.2024.100397","DOIUrl":"10.1016/j.xhgg.2024.100397","url":null,"abstract":"<p><p>Single-cell transcriptome data can provide insights into how genetic variation influences biological processes involved in human physiology and disease. However, the identification of gene-level associations in distinct cell types faces several challenges, including the limited reference resources from population-scale studies, data sparsity in single-cell RNA sequencing, and the complex cell state pattern of expression within individual cell types. Here, we develop genetic models of cell-type-specific and cell-state-adjusted gene expression in mid-brain neurons undergoing differentiation from induced pluripotent stem cells. The resulting framework quantifies the dynamics of the genetic regulation of gene expression and estimates its cell-type specificity. As an application, we show that the approach detects known and new genes associated with schizophrenia and enables insights into context-dependent disease mechanisms. We provide a genomic resource from a phenome-wide application of our models to more than 1,500 phenotypes from the UK Biobank. Using longitudinal, genetically determined expression, we implement a predictive causality framework, evaluating the prediction of future values of a target gene expression using prior values of a putative regulatory gene. Collectively, the results of this work demonstrate the insights that can be gained into the molecular underpinnings of disease by quantifying the genetic control of gene expression at single-cell resolution.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100397"},"PeriodicalIF":3.3,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915801","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":"Genome-wide maps of highly-similar intrachromosomal repeats that can mediate ectopic recombination in three human genome assemblies.","authors":"Luis Fernandez-Luna, Carlos Aguilar-Perez, Christopher M Grochowski, Michele G Mehaffey, Claudia M B Carvalho, Claudia Gonzaga-Jauregui","doi":"10.1016/j.xhgg.2024.100396","DOIUrl":"10.1016/j.xhgg.2024.100396","url":null,"abstract":"<p><p>Repeated sequences spread throughout the genome play important roles in shaping the structure of chromosomes and facilitating the generation of new genomic variation through structural rearrangements. Several mechanisms of structural variation formation use shared nucleotide similarity between repeated sequences as substrate for ectopic recombination. We performed genome-wide analyses of direct and inverted intrachromosomal repeated sequence pairs with 200 bp or more and 80% or greater sequence identity in three human genome assemblies, GRCh37, GRCh38, and T2T-CHM13. Overall, the composition and distribution of direct and inverted repeated sequences identified was similar among the three assemblies involving 13%-15% of the haploid genome, with an increased, albeit not significant, number of repeated sequences in T2T-CHM13. Interestingly, the majority of repeated sequences are below 1 kb in length with a median of 84.2% identity, highlighting the potential relevance of smaller, less identical repeats, such as Alu-Alu pairs, for ectopic recombination. We cross-referenced the identified repeated sequences with protein-coding genes to identify those at risk for being involved in genomic rearrangements. Olfactory receptors and immune response genes were enriched among those impacted.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100396"},"PeriodicalIF":3.3,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898716","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":"Evaluation of imputation performance of multiple reference panels in a Pakistani population.","authors":"Jiayi Xu, Dongjing Liu, Arsalan Hassan, Giulio Genovese, Alanna C Cote, Brian Fennessy, Esther Cheng, Alexander W Charney, James A Knowles, Muhammad Ayub, Roseann E Peterson, Tim B Bigdeli, Laura M Huckins","doi":"10.1016/j.xhgg.2024.100395","DOIUrl":"10.1016/j.xhgg.2024.100395","url":null,"abstract":"<p><p>Genotype imputation is crucial for genome-wide association studies (GWASs), but reference panels and existing benchmarking studies prioritize European individuals. Consequently, it is unclear which publicly available reference panel should be used for Pakistani individuals, and whether ancestry composition or sample size of the panel matters more for imputation accuracy. Our study compared different reference panels to impute genotype data in 1,814 Pakistani individuals, finding the best performance balancing accuracy and coverage with meta-imputation with TOPMed and the expanded 1000 Genomes (ex1KG) reference. Imputation accuracy of ex1KG outperformed TOPMed for common variants despite its 30-fold smaller sample size, supporting efforts to create future panels with diverse populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100395"},"PeriodicalIF":3.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855741","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":"A recurrent variant in PPP2R5C identified in individuals with macrocephaly, intellectual disability, and seizures.","authors":"Alison M Muir, Adi Reich, Fanggeng Zou, Deanna Alexis Carere, Sue Moyer Harasink, Lily Tran, Bobbi McGivern","doi":"10.1016/j.xhgg.2024.100394","DOIUrl":"10.1016/j.xhgg.2024.100394","url":null,"abstract":"<p><p>PPP2R5C encodes a B-type regulatory subunit of protein phosphatase 2A (PP2A). This protein serine/threonine phosphatase is a component of multiple signaling pathways and is an established negative regulator of cell division, growth, and proliferation. De novo variants in other subunits of PP2A are associated with neurodevelopment disorders and intellectual disability (ID). We report two unrelated affected individuals with a recurrent variant in PPP2R5C (c.457G>A: p.(Glu153Lys)). Core features in affected individuals include macrocephaly, ID, hypotonia, and seizures. The Glu153 residue is part of a highly conserved acidic loop and directly interacts with the PP2A catalytic subunit. Our results support heterozygous PPP2R5C missense variants as a potential cause of macrocephaly and neurodevelopmental disorder.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100394"},"PeriodicalIF":3.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855740","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":"An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome.","authors":"Tess Levy, J Lloyd Holder, Joseph P Horrigan, Michael F Snape, Alison McMorn, Christina Layton, Hailey Silver, Kate Friedman, Hannah Grosman, Slayton Underwood, Danielle Halpern, Jessica Zweifach, Paige M Siper, Alexander Kolevzon","doi":"10.1016/j.xhgg.2024.100393","DOIUrl":"10.1016/j.xhgg.2024.100393","url":null,"abstract":"<p><p>Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene. Approximately 25% of individuals with PMS have epilepsy. Treatment of epilepsy in PMS may require multiple anticonvulsants, and in a minority of cases, seizures remain poorly controlled. Converging lines of evidence in different experimental models indicate that the Ras-ERK pathway is implicated in the pathophysiology of seizure generation and neurobehavioral symptoms in PMS. The goal of this study was to evaluate the safety, tolerability, and efficacy in treating seizures in adults and adolescents with PMS using AMO-01, a Ras-ERK pathway inhibitor. A single 6-hour intravenous infusion of AMO-01 at 120 mg/m² was administered to six participants using an open-label design. Safety was assessed during the infusion and for 4 weeks post-infusion. Caregivers completed seizure diaries and recorded individual seizures during a baseline period and for 4 weeks following the infusion. Exploratory clinical and biomarker assessments were completed throughout the study. AMO-01 was well tolerated, with no serious adverse events (AEs) reported. All AEs were mild or moderate in severity. Seizures were reduced by at least 25% compared to baseline at each follow-up (weeks 1, 2, and 4). Exploratory clinical measures did not change significantly from baseline, but visual evoked potentials (VEPs) and phosphorylated ERK blood levels revealed trending changes in a subset of participants. These results provide preliminary support for the safety of AMO-01 and its efficacy in reducing seizures in adults with PMS. Future placebo-controlled studies with larger sample sizes and repeated dosing are warranted.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100393"},"PeriodicalIF":3.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847746","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":"Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection.","authors":"Eleanor Karp-Tatham, Callum R O'Neill, Julian C Knight, Alexander J Mentzer, Amanda Y Chong","doi":"10.1016/j.xhgg.2024.100382","DOIUrl":"10.1016/j.xhgg.2024.100382","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100382"},"PeriodicalIF":3.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568658","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}