HGG Advances最新文献_第7页

Quantifying negative selection on synonymous variants. 量化同义变体的负选择。

IF 4.4

HGG Advances Pub Date : 2024-04-11 Epub Date: 2024-01-08 DOI: 10.1016/j.xhgg.2024.100262

Mikhail Gudkov, Loïc Thibaut, Eleni Giannoulatou

{"title":"Quantifying negative selection on synonymous variants.","authors":"Mikhail Gudkov, Loïc Thibaut, Eleni Giannoulatou","doi":"10.1016/j.xhgg.2024.100262","DOIUrl":"10.1016/j.xhgg.2024.100262","url":null,"abstract":"Widespread adoption of DNA sequencing has resulted in large numbers of genetic variants, whose contribution to disease is not easily determined. Although many types of variation are known to disrupt cellular processes in predictable ways, for some categories of variants, the effects may not be directly detectable. A particular example is synonymous variants, that is, those single-nucleotide variants that create a codon substitution, such that the produced amino acid sequence is unaffected. Contrary to the original theory suggesting that synonymous variants are benign, there is a growing volume of research showing that, despite their \"silent\" mechanism of action, some synonymous variation may be deleterious. Here, we studied the extent of the negative selective pressure acting on different classes of synonymous variants by analyzing the relative enrichment of synonymous singleton variants in the human exomes provided by gnomAD. Using a modification of the mutability-adjusted proportion of singletons (MAPS) metric as a measure of purifying selection, we found that some classes of synonymous variants are subject to stronger negative selection than others. For instance, variants that reduce codon optimality undergo stronger selection than optimality-increasing variants. Besides, selection affects synonymous variants implicated in splice-site-loss or splice-site-gain events. To understand what drives this negative selection, we tested a number of predictors in the aim to explain the variability in the selection scores. Our findings provide insights into the effects of synonymous variants at the population level, highlighting the specifics of the role that these variants play in health and disease.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404654","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}

引用次数: 0

Placental expression quantitative trait loci in an East Asian population. 东亚人群的胎盘表达定量性状位点

IF 4.4

HGG Advances Pub Date : 2024-04-11 Epub Date: 2024-02-03 DOI: 10.1016/j.xhgg.2024.100276

Jaeyong Choi, Seung Mi Lee, Errol R Norwitz, Ji Hoi Kim, Young Mi Jung, Chan-Wook Park, Jong Kwan Jun, Dakyung Lee, Yongjoon Jin, Sookyung Kim, Bukyoung Cha, Joong Shin Park, Jong-Il Kim

{"title":"Placental expression quantitative trait loci in an East Asian population.","authors":"Jaeyong Choi, Seung Mi Lee, Errol R Norwitz, Ji Hoi Kim, Young Mi Jung, Chan-Wook Park, Jong Kwan Jun, Dakyung Lee, Yongjoon Jin, Sookyung Kim, Bukyoung Cha, Joong Shin Park, Jong-Il Kim","doi":"10.1016/j.xhgg.2024.100276","DOIUrl":"10.1016/j.xhgg.2024.100276","url":null,"abstract":"Expression quantitative trait loci (eQTL) analysis measures the contribution of genetic variation in gene expression on complex traits. Although this methodology has been used to examine gene regulation in numerous human tissues, eQTL research in solid tissues is relatively lacking. We conducted eQTL analysis on placentas collected from an East Asian population in an effort to identify gene regulatory mechanisms in this tissue. Placentas (n = 102) were collected at the time of cesarean delivery. mRNA was extracted, sequenced with NGS, and compared with matched maternal and fetal DNA arrays performed using maternal and neonatal cord blood. Linear regression modeling was performed using tensorQTL. Fine-mapping along with epigenomic annotation was used to select putative functional variants. We identified 2,703 coding genes that contained at least one eQTL with statistical significance (false discovery rate <0.05). After fine-mapping, we found 108 previously unreported eQTL variants with posterior inclusion probability >0.1. Of these, 19% were located in genomic regions with evidence from public placental epigenome suggesting that they may be functionally relevant. For example, variant rs28379289 located in the placenta-specific regulatory region changes the binding affinity of transcription factor leading to higher expression of LGALS3, which is known to affect placental function. This study expands the knowledge base of regulatory elements within the human placenta and identifies 108 previously unreported placenta eQTL signals, which are listed in our publicly available GMI eQTL database. Further studies are needed to identify and characterize genetic regulatory mechanisms that affect placental function in normal pregnancy and placenta-related diseases.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139681686","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}

引用次数: 0

Single-cell analysis identified POSTN⁺ cells associated with the aggressive phenotype and risk of esophageal squamous cell carcinoma. 单细胞分析发现与食管鳞状细胞癌侵袭性表型和风险相关的 POSTN+ 细胞

IF 4.4

HGG Advances Pub Date : 2024-04-11 Epub Date: 2024-02-18 DOI: 10.1016/j.xhgg.2024.100278

Yuqian Tan, Lina Song, Jialing Ma, Miaoxin Pan, Siyuan Niu, Xinying Yue, Yueping Li, Linglong Gu, Shasha Liu, Jiang Chang

{"title":"Single-cell analysis identified POSTN+ cells associated with the aggressive phenotype and risk of esophageal squamous cell carcinoma.","authors":"Yuqian Tan, Lina Song, Jialing Ma, Miaoxin Pan, Siyuan Niu, Xinying Yue, Yueping Li, Linglong Gu, Shasha Liu, Jiang Chang","doi":"10.1016/j.xhgg.2024.100278","DOIUrl":"10.1016/j.xhgg.2024.100278","url":null,"abstract":"Tumors are intricate and heterogeneous systems characterized by mosaic cancer cell populations with diverse expression profiles. Leveraging single-cell technologies, we employed the Scissor algorithm to delineate an epithelial subpopulation associated with the aggressive phenotype in esophageal squamous cell carcinoma (ESCC). This identified subpopulation exhibited elevated expression of genes involved in critical pathways, such as epithelial-mesenchymal transition and PI3K-Akt. Key signature genes within this subpopulation, namely CAV1, COL3A1, COL6A1, POSTN, and TAGLN, demonstrated significant upregulation concomitant with both tumorigenesis and tumor progression across independent single-cell datasets. Furthermore, we selected 1,450 expression quantitative trait loci of the top 62 signature genes of this cell subpopulation to investigate their potential in predicting ESCC risk. The results showed that the POSTN loci were predominantly associated with ESCC susceptibility. Through functional annotation and replication analyses, we identified that the rs1028728 in the POSTN promoter was significantly associated with increased ESCC risk in 7,049 ESCC cases and 8,063 controls (odds ratio = 1.29, 95% confidence interval: 1.18-1.42, p = 4.03 × 10-8). Subsequent biochemical experiments showed that the rs1028728[T] allele enhanced POSTN expression by affecting the binding of PRRX1 in the POSTN promoter. In summary, our meticulous single-cell analysis delineates an invasive epithelial subpopulation in ESCC, with POSTN emerging as an important marker for the aggressive phenotype. These findings offer more insights into potential strategies for the prevention and intervention of ESCC, enriching our understanding of this complex cancer landscape.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10924139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139900533","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}

引用次数: 0

Subset-based method for cross-tissue transcriptome-wide association studies improves power and interpretability. 基于子集的跨组织全转录组关联研究方法提高了研究效率和可解释性

IF 4.4

HGG Advances Pub Date : 2024-04-11 Epub Date: 2024-03-16 DOI: 10.1016/j.xhgg.2024.100283

Xinyu Guo, Nilanjan Chatterjee, Diptavo Dutta

{"title":"Subset-based method for cross-tissue transcriptome-wide association studies improves power and interpretability.","authors":"Xinyu Guo, Nilanjan Chatterjee, Diptavo Dutta","doi":"10.1016/j.xhgg.2024.100283","DOIUrl":"10.1016/j.xhgg.2024.100283","url":null,"abstract":"Integrating results from genome-wide association studies (GWASs) and studies of molecular phenotypes such as gene expressions can improve our understanding of the biological functions of trait-associated variants and can help prioritize candidate genes for downstream analysis. Using reference expression quantitative trait locus (eQTL) studies, several methods have been proposed to identify gene-trait associations, primarily based on gene expression imputation. To increase the statistical power by leveraging substantial eQTL sharing across tissues, meta-analysis methods aggregating such gene-based test results across multiple tissues or contexts have been developed as well. However, most existing meta-analysis methods have limited power to identify associations when the gene has weaker associations in only a few tissues and cannot identify the subset of tissues in which the gene is \"activated.\" For this, we developed a cross-tissue subset-based transcriptome-wide association study (CSTWAS) meta-analysis method that improves power under such scenarios and can extract the set of potentially associated tissues. To improve applicability, CSTWAS uses only GWAS summary statistics and pre-computed correlation matrices to identify a subset of tissues that have the maximal evidence of gene-trait association. Through numerical simulations, we found that CSTWAS can maintain a well-calibrated type-I error rate, improves power especially when there is a small number of associated tissues for a gene-trait association, and identifies an accurate associated tissue set. By analyzing GWAS summary statistics of three complex traits and diseases, we demonstrate that CSTWAS could identify biological meaningful signals while providing an interpretation of disease etiology by extracting a set of potentially associated tissues.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10999697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140140910","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}

引用次数: 0

Evaluating and improving health equity and fairness of polygenic scores. 评估和改善多基因评分的健康公平性和公正性。

IF 3.3

HGG Advances Pub Date : 2024-04-11 Epub Date: 2024-02-23 DOI: 10.1016/j.xhgg.2024.100280

Tianyu Zhang, Geyu Zhou, Lambertus Klei, Peng Liu, Alexandra Chouldechova, Hongyu Zhao, Kathryn Roeder, Max G'Sell, Bernie Devlin

{"title":"Evaluating and improving health equity and fairness of polygenic scores.","authors":"Tianyu Zhang, Geyu Zhou, Lambertus Klei, Peng Liu, Alexandra Chouldechova, Hongyu Zhao, Kathryn Roeder, Max G'Sell, Bernie Devlin","doi":"10.1016/j.xhgg.2024.100280","DOIUrl":"10.1016/j.xhgg.2024.100280","url":null,"abstract":"Polygenic scores (PGSs) are quantitative metrics for predicting phenotypic values, such as human height or disease status. Some PGS methods require only summary statistics of a relevant genome-wide association study (GWAS) for their score. One such method is Lassosum, which inherits the model selection advantages of Lasso to select a meaningful subset of the GWAS single-nucleotide polymorphisms as predictors from their association statistics. However, even efficient scores like Lassosum, when derived from European-based GWASs, are poor predictors of phenotype for subjects of non-European ancestry; that is, they have limited portability to other ancestries. To increase the portability of Lassosum, when GWAS information and estimates of linkage disequilibrium are available for both ancestries, we propose Joint-Lassosum (JLS). In the simulation settings we explore, JLS provides more accurate PGSs compared to other methods, especially when measured in terms of fairness. In analyses of UK Biobank data, JLS was computationally more efficient but slightly less accurate than a Bayesian comparator, SDPRX. Like all PGS methods, JLS requires selection of predictors, which are determined by data-driven tuning parameters. We describe a new approach to selecting tuning parameters and note its relevance for model selection for any PGS. We also draw connections to the literature on algorithmic fairness and discuss how JLS can help mitigate fairness-related harms that might result from the use of PGSs in clinical settings. While no PGS method is likely to be universally portable, due to the diversity of human populations and unequal information content of GWASs for different ancestries, JLS is an effective approach for enhancing portability and reducing predictive bias.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10937319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139944482","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}

引用次数: 0

PABPN1 loss-of-function causes APA-shift in oculopharyngeal muscular dystrophy. PABPN1功能缺失会导致眼咽肌营养不良症的APA移位。

IF 4.4

HGG Advances Pub Date : 2024-04-11 Epub Date: 2024-01-11 DOI: 10.1016/j.xhgg.2024.100269

Milad Shademan, Hailiang Mei, Baziel van Engelen, Yavuz Ariyurek, Susan Kloet, Vered Raz

{"title":"PABPN1 loss-of-function causes APA-shift in oculopharyngeal muscular dystrophy.","authors":"Milad Shademan, Hailiang Mei, Baziel van Engelen, Yavuz Ariyurek, Susan Kloet, Vered Raz","doi":"10.1016/j.xhgg.2024.100269","DOIUrl":"10.1016/j.xhgg.2024.100269","url":null,"abstract":"Alternative polyadenylation (APA) at the 3' UTR of transcripts contributes to the cell transcriptome. APA is suppressed by the nuclear RNA-binding protein PABPN1. Aging-associated reduced PABPN1 levels in skeletal muscles lead to muscle wasting. Muscle weakness in oculopharyngeal muscular dystrophy (OPMD) is caused by short alanine expansion in PABPN1 exon1. The expanded PABPN1 forms nuclear aggregates, an OPMD hallmark. Whether the expanded PABPN1 affects APA and how it contributes to muscle pathology is unresolved. To investigate these questions, we developed a procedure including RNA library preparation and a simple pipeline calculating the APA-shift ratio as a readout for PABPN1 activity. Comparing APA-shift results to previously published PAS utilization and APA-shift results, we validated this procedure. The procedure was then applied on the OPMD cell model and on RNA from OPMD muscles. APA-shift was genome-wide in the mouse OPMD model, primarily affecting muscle transcripts. In OPMD individuals, APA-shift was enriched with muscle transcripts. In an OPMD cell model APA-shift was not significant. APA-shift correlated with reduced expression levels of a subset of PABPN1 isoforms, whereas the expression of the expanded PABPN1 did not correlate with APA-shift. PABPN1 activity is not affected by the expression of expanded PABPN1, but rather by reduced PABPN1 expression levels. In muscles, PABPN1 activity initially affects muscle transcripts. We suggest that muscle weakness in OPMD is caused by PABPN1 loss-of-function leading to APA-shift that primarily affects in muscle transcripts.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10840355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139425631","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}

引用次数: 0

Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis. "共享基因组片段分析表明，MHC I 类和 III 类分子是幼年特发性关节炎的遗传风险因素。

IF 4.4

HGG Advances Pub Date : 2024-04-11 Epub Date: 2024-02-18 DOI: 10.1016/j.xhgg.2024.100277

Cecile N Avery, Nicole D Russell, Cody J Steely, Aimee O Hersh, John F Bohnsack, Sampath Prahalad, Lynn B Jorde

{"title":"Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis.","authors":"Cecile N Avery, Nicole D Russell, Cody J Steely, Aimee O Hersh, John F Bohnsack, Sampath Prahalad, Lynn B Jorde","doi":"10.1016/j.xhgg.2024.100277","DOIUrl":"10.1016/j.xhgg.2024.100277","url":null,"abstract":"Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease encompassing several clinically defined subtypes of varying severity. The etiology of JIA remains largely unknown, but genome-wide association studies (GWASs) have identified up to 22 genes associated with JIA susceptibility, including a well-established association with HLA-DRB1. Continued investigation of heritable risk factors has been hindered by disease heterogeneity and low disease prevalence. In this study, we utilized shared genomic segments (SGS) analysis on whole-genome sequencing of 40 cases from 12 multi-generational pedigrees significantly enriched for JIA. Subsets of cases are connected by a common ancestor in large extended pedigrees, increasing the power to identify disease-associated loci. SGS analysis identifies genomic segments shared among disease cases that are likely identical by descent and anchored by a disease locus. This approach revealed statistically significant signals for major histocompatibility complex (MHC) class I and class III alleles, particularly HLA-A∗02:01, which was observed at a high frequency among cases. Furthermore, we identified an additional risk locus at 12q23.2-23.3, containing genes primarily expressed by naive B cells, natural killer cells, and monocytes. The recognition of additional risk beyond HLA-DRB1 provides a new perspective on immune cell dynamics in JIA. These findings contribute to our understanding of JIA and may guide future research and therapeutic strategies.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10918567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139900532","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}

引用次数: 0

Improved estimation of functional enrichment in SNP heritability using feasible generalized least squares. 利用可行的广义最小二乘法改进 SNP 遗传性中功能富集的估算。

IF 4.4

HGG Advances Pub Date : 2024-04-11 Epub Date: 2024-02-07 DOI: 10.1016/j.xhgg.2024.100272

Zewei Xiong, Thuan-Quoc Thach, Yan Dora Zhang, Pak Chung Sham

{"title":"Improved estimation of functional enrichment in SNP heritability using feasible generalized least squares.","authors":"Zewei Xiong, Thuan-Quoc Thach, Yan Dora Zhang, Pak Chung Sham","doi":"10.1016/j.xhgg.2024.100272","DOIUrl":"10.1016/j.xhgg.2024.100272","url":null,"abstract":"Functional enrichment results typically implicate tissue or cell-type-specific biological pathways in disease pathogenesis and as therapeutic targets. We propose generalized linkage disequilibrium score regression (g-LDSC) that requires only genome-wide association studies (GWASs) summary-level data to estimate functional enrichment. The method adopts the same assumptions and regression model formulation as stratified linkage disequilibrium score regression (s-LDSC). Although s-LDSC only partially uses LD information, our method uses the whole LD matrix, which accounts for possible correlated error structure via a feasible generalized least-squares estimation. We demonstrate through simulation studies under various scenarios that g-LDSC provides more precise estimates of functional enrichment than s-LDSC, regardless of model misspecification. In an application to GWAS summary statistics of 15 traits from the UK Biobank, estimates of functional enrichment using g-LDSC were lower and more realistic than those obtained from s-LDSC. In addition, g-LDSC detected more significantly enriched functional annotations among 24 functional annotations for the 15 traits than s-LDSC (118 vs. 51).","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10901842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139703613","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}

引用次数: 0

Return of polygenic risk scores in research: Stakeholders' views on the eMERGE-IV study. 多基因风险评分在研究中的回归：利益相关者对 eMERGE-IV 研究的看法。

IF 4.4

HGG Advances Pub Date : 2024-04-11 Epub Date: 2024-02-27 DOI: 10.1016/j.xhgg.2024.100281

Maya Sabatello, Suzanne Bakken, Wendy K Chung, Elizabeth Cohn, Katherine D Crew, Krzysztof Kiryluk, Rita Kukafka, Chunhua Weng, Paul S Appelbaum

{"title":"Return of polygenic risk scores in research: Stakeholders' views on the eMERGE-IV study.","authors":"Maya Sabatello, Suzanne Bakken, Wendy K Chung, Elizabeth Cohn, Katherine D Crew, Krzysztof Kiryluk, Rita Kukafka, Chunhua Weng, Paul S Appelbaum","doi":"10.1016/j.xhgg.2024.100281","DOIUrl":"10.1016/j.xhgg.2024.100281","url":null,"abstract":"Research on polygenic risk scores (PRSs) for common, genetically complex chronic diseases aims to improve health-related predictions, tailor risk-reducing interventions, and improve health outcomes. Yet, the study and use of PRSs in clinical settings raise equity, clinical, and regulatory challenges that can be greater for individuals from historically marginalized racial, ethnic, and other minoritized communities. As part of the National Human Genome Research Institute-funded Electronic Medical Records and Genomics IV Network, we conducted online focus groups with patients/community members, clinicians, and members of institutional review boards to explore their views on key issues, including PRS research, return of PRS results, clinical translation, and barriers and facilitators to health behavioral changes in response to PRS results. Across stakeholder groups, our findings indicate support for PRS development and a strong interest in having PRS results returned to research participants. However, we also found multi-level barriers and significant differences in stakeholders' views about what is needed and possible for successful implementation. These include researcher-participant interaction formats, health and genomic literacy, and a range of structural barriers, such as financial instability, insurance coverage, and the absence of health-supporting infrastructure and affordable healthy food options in poorer neighborhoods. Our findings highlight the need to revisit and implement measures in PRS studies (e.g., incentives and resources for follow-up care), as well as system-level policies to promote equity in genomic research and health outcomes.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10950748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139984073","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}

引用次数: 0

Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay. 利用稳健的 PS3/BS3 功能膜片钳测定法对 KCNH2 变异进行临床解读。

IF 4.4

HGG Advances Pub Date : 2024-04-11 Epub Date: 2024-01-14 DOI: 10.1016/j.xhgg.2024.100270

Kate L Thomson, Connie Jiang, Ebony Richardson, Dominik S Westphal, Tobias Burkard, Cordula M Wolf, Matteo Vatta, Steven M Harrison, Jodie Ingles, Connie R Bezzina, Brett M Kroncke, Jamie I Vandenberg, Chai-Ann Ng

{"title":"Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.","authors":"Kate L Thomson, Connie Jiang, Ebony Richardson, Dominik S Westphal, Tobias Burkard, Cordula M Wolf, Matteo Vatta, Steven M Harrison, Jodie Ingles, Connie R Bezzina, Brett M Kroncke, Jamie I Vandenberg, Chai-Ann Ng","doi":"10.1016/j.xhgg.2024.100270","DOIUrl":"10.1016/j.xhgg.2024.100270","url":null,"abstract":"Long QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes, there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch-clamp assay to facilitate classification of missense variants in KCNH2, one of the key LQTS genes. A curated set of 30 benign and 30 pathogenic missense variants were used to establish the range of normal and abnormal function. The extent to which variants reduced protein function was quantified using Z scores, the number of standard deviations from the mean of the normalized current density of the set of benign variant controls. A Z score of -2 defined the threshold for abnormal loss of function, which corresponds to 55% wild-type function. More extreme Z scores were observed for variants with a greater loss-of-function effect. We propose that the Z score for each variant can be used to inform the application and weighting of abnormal and normal functional evidence criteria (PS3 and BS3) within the American College of Medical Genetics and Genomics variant classification framework. The validity of this approach was demonstrated using a series of 18 KCNH2 missense variants detected in a childhood onset LQTS cohort, where the level of function assessed using our assay correlated to the Schwartz score (a scoring system used to quantify the probability of a clinical diagnosis of LQTS) and the length of the corrected QT (QTc) interval.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10840334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466191","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}

引用次数: 0