American journal of human genetics最新文献

{"title":"Bayesian causal graphical model for joint Mendelian randomization analysis of multiple exposures and outcomes.","authors":"Verena Zuber, Toinét Cronjé, Na Cai, Dipender Gill, Leonardo Bottolo","doi":"10.1016/j.ajhg.2025.03.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.005","url":null,"abstract":"<p><p>Current Mendelian randomization (MR) methods do not reflect complex relationships among multiple exposures and outcomes as is typical for real-life applications. We introduce MrDAG, a Bayesian causal graphical model for summary-level MR analysis to detect dependency relations within the exposures, the outcomes, and between them to improve causal effects estimation. MrDAG combines three causal inference strategies. It uses genetic variation as instrumental variables to account for unobserved confounders. It performs structure learning to detect and orientate the direction of the dependencies within the exposures and the outcomes. Finally, interventional calculus is employed to derive principled causal effect estimates. In MrDAG the directionality of the causal effects between the exposures and the outcomes is assumed known, i.e., the exposures can only be potential causes of the outcomes, and no reverse causation is allowed. In the simulation study, MrDAG outperforms recently proposed one-outcome-at-a-time and multi-response multi-variable Bayesian MR methods as well as causal graphical models under the constraint on edges' orientation from the exposures to the outcomes. MrDAG was motivated to unravel how lifestyle and behavioral exposures impact mental health. It highlights first, education and second, smoking as effective points of intervention given their important downstream effects on mental health. It also enables the identification of a novel path between smoking and the genetic liability to schizophrenia and cognition, demonstrating the complex pathways toward mental health. These insights would have been impossible to delineate without modeling the paths between multiple exposures and outcomes at once.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increasing the genomic workforce through research capacity building: Designing evaluation plans for maximum impact.","authors":"Karyn J Roberts, Weini Ogbagiorgis, Angela Sy, Sarah Williams-Blangero, LaMonica V Stewart, Eron Manusov, Sofia B Fernandez, Rachel D Clarke, Ebony B Madden","doi":"10.1016/j.ajhg.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.002","url":null,"abstract":"<p><p>More interventions are needed to address the need for workforce diversity and research capacity building (RCB) in genomics. In 2023, the National Human Genome Research Institute and the National Institute on Minority Health and Health Disparities of the National Institutes of Health funded the Diversity Centers for Genome Research Consortium to address this critical gap. The NIH program staff designed a prospective evaluation plan and developed common data elements (CDEs) that capture common evaluation outputs, synergize and streamline reporting, and facilitate continuous quality improvement. We created five CDEs: genomics programs and equipment, scientific productivity, scientific collaboration, community engagement, and workforce development. The prospective development of an evaluation plan based on CDEs facilitates the ongoing evaluation, reporting, and adjustment of RCB interventions to enhance the diversity of the genomics workforce.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-cost generation of clinical-grade, layperson-friendly pharmacogenetic passports using oligonucleotide arrays.","authors":"Pauline Lanting, Robert Warmerdam, Jelle Slager, Harm Brugge, Taichi Ochi, Marloes Benjamins, Esteban Lopera-Maya, Soesma Jankipersadsing, Jody Gelderloos-Arends, Daphne Teuben, Dennis Hendriksen, Bart Charbon, Lennart Johansson, Thijs Oude Munnink, Nienke de Boer-Veger, Bob Wilffert, Morris Swertz, Daan Touw, Patrick Deelen, Nine Knoers, Jackie Dekens, Lude Franke","doi":"10.1016/j.ajhg.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.003","url":null,"abstract":"<p><p>Pharmacogenomic (PGx) information is essential for precision medicine, enabling drug prescriptions to be personalized according to an individual's genetic background. Almost all individuals will carry a genetic marker that affects their drug response, so the ideal drug prescription for these individuals will differ from the population-level guidelines. Currently, PGx information is often not available at first prescription, reducing its effectiveness. In the Netherlands, pharmacogenetic information is most often obtained using dedicated single-gene assays, making it expensive and time consuming to generate complete multi-gene PGx profiles. We therefore hypothesized that we could also use genome-wide oligonucleotide genotyping arrays to generate comprehensive PGx information (PGx passports), thereby decreasing the cost and time required for PGx testing and lowering the barrier to generating PGx information prior to first prescription. Taking advantage of existing genetic data generated in two biobanks, we developed and validated Asterix, a low-cost, clinical-grade PGx passport pipeline for 12 PGx genes. In these biobanks, we performed and clinically validated genetic variant calling and statistical phasing and imputation. In addition, we developed and validated a CYP2D6 copy-number-variant-calling tool, forgoing the need to use separate PCR-based copy-number detection. Ultimately, we returned 1,227 PGx passports to biobank participants via a layperson-friendly app, improving knowledge of PGx among citizens. Our study demonstrates the feasibility of a low-cost, clinical-grade PGx passport pipeline that could be readily implemented in clinical settings to enhance personalized healthcare, ensuring that patients receive the most effective and safe drug therapy based on their unique genetic makeup.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay and cooperation between GLI2 and master transcription factors promote progression of esophageal squamous cell carcinoma.","authors":"Yin-Qiao Liu, Ze-Jun Zheng, Wang-Kai Fang, Yan-Shang Li, Chun Li, Min Yang, Dong-Chen Han, Jun-Hua Zhou, Ying-Hua Xie, Yu-Ying Zhang, Zhuo-Ying Kang, Yi-Wei Xu, Jian-Jun Xie","doi":"10.1016/j.ajhg.2025.03.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.001","url":null,"abstract":"<p><p>The establishment of gene expression programs that drive cell identity is governed by tightly regulated transcription factors (TFs) that engage in auto- and cross-regulation in a feedforward manner, forming core regulatory circuitries (CRCs). Here, we identify and validate an important interconnected CRC formed by three master TFs-GLI2, TP63, and RUNX1-in esophageal squamous cell carcinoma (ESCC). Furthermore, master TFs co-bind to their own and each other's super-enhancers, forming an interconnected auto-regulatory loop. Mechanistically, these master TFs occupy the majority of ESCC super-enhancers and cooperatively orchestrate the ESCC transcription program. Functionally, GLI2, a master TF, is essential for ESCC viability, migration, invasion, and the growth of xenograft tumors. Moreover, the overexpression of GLI2 is significantly associated with shorter overall survival of patients with ESCC. Downstream, this CRC apparatus coordinately regulates gene expression networks in ESCC, controlling important cancer-promoting pathways, including Hedgehog, glycolysis, and epidermal growth factor receptor signaling pathways. Together, these findings offer significant mechanistic insights into the transcriptional dysregulation in ESCC and recognize GLI2 as a potential therapeutic target and prognostic marker for ESCC. More importantly, CRC-downstream genes and signaling pathways may contain potential therapeutic targets for this malignancy.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine-mapping in admixed populations using CARMA-X, with applications to Latin American studies.","authors":"Zikun Yang, Chen Wang, Yuridia Selene Posadas-Garcia, Valeria Añorve-Garibay, Badri Vardarajan, Andrés Moreno Estrada, Mashaal Sohail, Richard Mayeux, Iuliana Ionita-Laza","doi":"10.1016/j.ajhg.2025.02.020","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.02.020","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) in ancestrally diverse populations are rapidly expanding, opening up unique opportunities for novel gene discoveries and increased utility of genetic findings in non-European individuals. A popular technique to identify putative causal variants at GWAS loci is via statistical fine-mapping. Despite tremendous efforts, fine-mapping remains a very challenging task, even in the relatively simple scenario of studies with a single, homogeneous population. For studies with admixed individuals, such as within Latin America and the Caribbean, methods for gene discovery are still limited. Here, we propose a Bayesian model for fine-mapping in admixed populations, CARMA-X, that addresses some of the unique challenges of admixed individuals. The proposed method includes an estimation method for the linkage disequilibrium (LD) matrix that accounts for small reference panels for admixed individuals, heterogeneity across populations and cross-ancestry LD, and a Bayesian hypothesis test that leads to robust fine-mapping when relying on external reference panels of modest size for LD estimation. Using simulations, we compare performance with recently proposed fine-mapping methods for multi-ancestry studies and show that the proposed model provides higher power while controlling false discoveries, especially when using an out-of-sample LD matrix. We further illustrate our approach through applications to two Latin American genetic studies, the Estudio Familiar de Influencia Genética en Alzheimer (EFIGA) study in the Dominican Republic and the Mexican Biobank, where we show the benefit of modeling ancestry-specific effects by prioritizing putative causal variants and genes, including several findings driven by ancestry-specific effects in the African and Native American ancestries.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consensus guidelines for assessing eligibility of pathogenic DNA variants for antisense oligonucleotide treatments.","authors":"David Cheerie, Margaret M Meserve, Danique Beijer, Charu Kaiwar, Logan Newton, Ana Lisa Taylor Tavares, Aubrie Soucy Verran, Emma Sherrill, Stefanie Leonard, Stephan J Sanders, Emily Blake, Nour Elkhateeb, Aastha Gandhi, Nicole S Y Liang, Jack T Morgan, Anna Verwillow, Jan Verheijen, Andrew Giles, Sean Williams, Maya Chopra, Laura Croft, Hormos Salimi Dafsari, Alice E Davidson, Jennifer Friedman, Anne Gregor, Bushra Haque, Rosan Lechner, Kylie-Ann Montgomery, Mina Ryten, Emil Schober, Gabriele Siegel, Patricia J Sullivan, Ella F Whittle, Bianca Zardetto, Timothy W Yu, Matthis Synofzik, Annemieke Aartsma-Rus, Gregory Costain, Marlen C Lauffer","doi":"10.1016/j.ajhg.2025.02.017","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.02.017","url":null,"abstract":"<p><p>Of the around 7,000 known rare diseases worldwide, disease-modifying treatments are available for fewer than 5%, leaving millions of individuals without specialized therapeutic strategies. In recent years, antisense oligonucleotides (ASOs) have shown promise as individualized genetic interventions for rare genetic diseases. However, there is currently no consensus on which disease-causing DNA variants are suitable candidates for this type of genetic therapy. The patient identification working group of the N=1 Collaborative (N1C), alongside an international group of volunteer assessors, has developed and piloted consensus guidelines for assessing the eligibility of pathogenic DNA variants for ASO treatments. We herein present the N1C VARIANT (variant assessments toward eligibility for antisense oligonucleotide treatment) guidelines, including the guiding scientific principles and our approach to consensus building. Pathogenic, disease-causing variants can be assessed for the three currently best-established ASO treatment approaches: splice correction, exon skipping, and downregulation of RNA transcripts. A genetic variant is classified as \"eligible,\" \"likely eligible,\" \"unlikely eligible,\" or \"not eligible\" in relation to the different approaches or as \"unable to assess.\" We also review key considerations related to assessing the upregulation of transcripts from the wild-type allele, an emerging ASO therapeutic strategy. We provide additional tools and training materials to enable clinicians and researchers to use these guidelines for their eligibility assessments. With this initial edition of our N1C VARIANT guidelines, we provide the rare genetic disease community with guidance on how to identify suitable candidates for variant-specific ASO-based therapies and the possibility of integrating such assessments into routine clinical practice.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2024 ASHG awards and addresses.","authors":"","doi":"10.1016/j.ajhg.2025.01.023","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.01.023","url":null,"abstract":"<p><p>Each year at the annual meeting of The American Society of Human Genetics (ASHG), addresses are given in honor of the Society and several award winners. A summary of each of these is provided below. On the following pages, we have printed the Presidential Address as well as the addresses for the Lifetime Achievement, Scientific Achievement, and Leadership awards. Recordings of these addresses, as well as those of many other presentations, can be found at http://www.ashg.org.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 3","pages":"459-460"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2024 Lifetime Achievement Award: Biology unbalanced: Genes, gene dosage, and disease susceptibility.","authors":"James R Lupski","doi":"10.1016/j.ajhg.2025.01.025","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.01.025","url":null,"abstract":"<p><p>This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. A video of the original address can be found at the ASHG website.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 3","pages":"467-469"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isogenic hiPSC models of Turner syndrome development reveal shared roles of inactive X and Y in the human cranial neural crest network.","authors":"Darcy T Ahern, Prakhar Bansal, Isaac V Faustino, Owen M Chambers, Erin C Banda, Heather R Glatt-Deeley, Rachael E Massey, Yuvabharath Kondaveeti, Stefan F Pinter","doi":"10.1016/j.ajhg.2025.01.013","DOIUrl":"10.1016/j.ajhg.2025.01.013","url":null,"abstract":"<p><p>Viable human aneuploidy can be challenging to model in rodents due to syntenic boundaries or primate-specific biology. Human monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which in contrast remain unaffected in X-monosomic mice. To learn how monosomy-X may impact embryonic development, we turned to 45,X and isogenic euploid human induced pluripotent stem cells (hiPSCs) from male and female mosaic donors. Because the neural crest (NC) is hypothesized to give rise to craniofacial and cardiovascular changes in TS, we assessed differential expression of hiPSC-derived anterior NC cells (NCCs). Across three independent isogenic panels, 45,X NCCs show impaired acquisition of PAX7⁺SOX10⁺ markers and disrupted expression of other NCC-specific genes relative to isogenic euploid controls. Additionally, 45,X NCCs increase cholesterol biosynthesis genes while reducing transcripts with 5' terminal oligopyrimidine (TOP) motifs, including those of ribosomal and nuclear-encoded mitochondrial proteins. Such metabolic pathways are also over-represented in weighted co-expression modules that are preserved in monogenic neurocristopathy and reflect 28% of all TS-associated terms of the human phenotype ontology. We demonstrate that 45,X NCCs reduce protein synthesis despite activation of mammalian target of rapamycin (mTOR) but are partially rescued by mild mTOR suppression. Our analysis identifies specific sex-linked genes that are expressed from two copies in euploid males and females alike and qualify as candidate haploinsufficient drivers of TS phenotypes in NC-derived lineages. This study demonstrates that isogenic hiPSC-derived NCC panels representing monosomy-X can serve as powerful models of early NC development in TS and inform new hypotheses toward its etiology.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"615-629"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct explanations underlie gene-environment interactions in the UK Biobank.","authors":"Arun Durvasula, Alkes L Price","doi":"10.1016/j.ajhg.2025.01.014","DOIUrl":"10.1016/j.ajhg.2025.01.014","url":null,"abstract":"<p><p>The role of gene-environment (GxE) interaction in disease and complex trait architectures is widely hypothesized but currently unknown. Here, we apply three statistical approaches to quantify and distinguish three different types of GxE interaction for a given trait and environmental (E) variable. First, we detect locus-specific GxE interaction by testing for genetic correlation (r_g) < 1 across E bins. Second, we detect genome-wide effects of the E variable on genetic variance by leveraging polygenic risk scores (PRSs) to test for significant PRSxE in a regression of phenotypes on PRS, E, and PRSxE, together with differences in SNP heritability across E bins. Third, we detect genome-wide proportional amplification of genetic and environmental effects as a function of the E variable by testing for significant PRSxE with no differences in SNP heritability across E bins. We applied our framework to 33 UK Biobank traits (25 quantitative traits and 8 diseases; average n = 325,000) and 10 E variables spanning lifestyle, diet, and other environmental exposures. First, we identified 19 trait-E pairs with r_g significantly <1 (false discovery rate < 5%); 28 trait-E pairs with significant PRSxE and significant SNP heritability differences across E bins; and 15 trait-E pairs with significant PRSxE but no SNP heritability differences across E bins. Across the three scenarios, eight of the trait-E pairs involved disease traits, whose interpretation is complicated by scale effects. Analyses using biological sex as the E variable produced additional significant findings in each of these scenarios. Overall, we infer a significant contribution of GxE and GxSex effects to complex trait variance.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"644-658"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}