American journal of human genetics最新文献

{"title":"Multiple origins and phenotypic implications of an extended human pseudoautosomal region shown by analysis of the UK Biobank.","authors":"Nitikorn Poriswanish, James Eales, Xiaoguang Xu, David Scannali, Rita Neumann, Jon H Wetton, Maciej Tomaszewski, Mark A Jobling, Celia A May","doi":"10.1016/j.ajhg.2025.01.026","DOIUrl":"10.1016/j.ajhg.2025.01.026","url":null,"abstract":"<p><p>The 2.7-Mb major pseudoautosomal region (PAR1) on the short arms of the human X and Y chromosomes plays a critical role in meiotic sex chromosome segregation and male fertility and has been regarded as evolutionarily stable. However, some European Y chromosomes belonging to Y haplogroups (Y-Hgs) R1b and I2a carry an ∼115-kb extension (ePAR [extended PAR]) arising from X-Y non-allelic homologous recombination (NAHR). To investigate the diversity, history, and dynamics of ePAR formation, we screened for its presence, and that of the predicted reciprocal X chromosome deletion, among ∼218,300 46,XY males of the UK Biobank (UKB), a cohort associated with longitudinal clinical data. The UKB incidence of ePAR is ∼0.77%, and that of the deletion is ∼0.02%. We found that Y-Hg I2a sub-lineages accounted for nearly 90% of ePAR cases but, by Y haplotyping and breakpoint sequencing, determined that, in total, there have been at least 18 independent ePAR origins, associated with nine different Y-Hgs. We found examples of ePAR linked to Y-Hg K among men of self-declared Pakistani ancestry and Y-Hg E1, typical of men with African ancestry, showing that ePAR is not restricted to Europeans. ePAR formation is likely random, with high frequencies in some Y-Hgs arising through drift and male-mediated expansions. Sequencing recombination junction fragments identified likely reciprocal events, and the heterogeneity of ePAR and X-deletion junctions highlighted the recurrent nature of the NAHR events. A phenome-wide association study revealed an association between ePAR and elevated levels of circulating IGF-1 as well as musculoskeletal phenotypes.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"927-939"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472250","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":"Clinical validation of RNA sequencing for Mendelian disorder diagnostics.","authors":"Sen Zhao, Kristina Macakova, Jefferson C Sinson, Hongzheng Dai, Jill Rosenfeld, Gladys E Zapata, Shenglan Li, Patricia A Ward, Christiana Wang, Chunjing Qu, Becky Maywald, Brendan Lee, Christine Eng, Pengfei Liu","doi":"10.1016/j.ajhg.2025.02.006","DOIUrl":"10.1016/j.ajhg.2025.02.006","url":null,"abstract":"<p><p>Despite rapid advancements in clinical sequencing, over half of diagnostic evaluations still lack definitive results. RNA sequencing (RNA-seq) has shown promise in research settings for bridging this gap by providing essential functional data for accurate interpretation of diagnostic sequencing results. However, despite advanced research pipelines, clinical translation of diagnostic RNA-seq has not yet been realized. We have developed and validated a clinical diagnostic RNA-seq test for individuals with suspected genetic disorders who have existing or concurrent comprehensive DNA diagnostic testing. This diagnostic RNA-seq test processes RNA samples from fibroblasts or blood and derives clinical interpretations based on the analytical detection of outliers in gene expressions and splicing patterns. The clinical validation involves 130 samples, including 90 negative and 40 positive samples. We developed provisional expression and splicing benchmarks using short-read and long-read RNA-seq data from the GM24385 lymphoblastoid sample produced by the Genome in a Bottle Consortium. For clinical validation, we first established reference ranges for each gene and junction based on expression distributions from our control data. We then evaluated the clinical performance of our outlier-based pipeline using 40 positive samples with previously identified diagnostic findings from the Undiagnosed Diseases Network project. Our study provides a paradigm and necessary resources for independent laboratories to validate a clinical RNA-seq test.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"779-792"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565790","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":"The contribution of coding variants to the heritability of multiple cancer types using UK Biobank whole-exome sequencing data.","authors":"Naomi Wilcox, Jonathan P Tyrer, Joe Dennis, Xin Yang, John R B Perry, Eugene J Gardner, Douglas F Easton","doi":"10.1016/j.ajhg.2025.02.013","DOIUrl":"10.1016/j.ajhg.2025.02.013","url":null,"abstract":"<p><p>Genome-wide association studies have been highly successful at identifying common variants associated with cancer; however, they do not explain all the inherited risks of cancer. Family-based studies, targeted sequencing, and, more recently, exome-wide association studies have identified rare coding variants in some genes associated with cancer risk, but the overall contribution of these variants to the heritability of cancer is less clear. Here, we describe a method to estimate the genome-wide contribution of rare coding variants to heritability that fits models to the burden effect sizes using an empirical Bayesian approach. We apply this method to the burden of protein-truncating variants in over 15,000 genes for 11 cancers in the UK Biobank using whole-exome sequencing data on over 400,000 individuals. We extend the method to consider the overlap of genes contributing to pairs of cancers. We found ovarian cancer to have the greatest proportion of heritability attributable to protein-truncating variants in genes (46%). The joint cancer models highlight significant clustering of cancer types, including a near-complete overlap in susceptibility genes for breast, ovarian, prostate, and pancreatic cancer. Our results provide insights into the contribution of rare coding variants to the heritability of cancer and identify additional genes with strong evidence of susceptibility to multiple cancer types.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"903-912"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613023","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":"EndoPRS: Incorporating endophenotype information to improve polygenic risk scores for clinical endpoints-A study in asthma.","authors":"Elena V Kharitonova,Quan Sun,Franklin Ockerman,Brian Chen,Laura Y Zhou,Micah R Hysong,Bjoernar Tuftin,Hongyuan Cao,Rasika A Mathias,Paul L Auer,Carole Ober,Laura M Raffield,Alexander P Reiner,Nancy J Cox,Samir N P Kelada,Ran Tao,Yun Li","doi":"10.1016/j.ajhg.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.008","url":null,"abstract":"Polygenic risk score (PRS) prediction of complex diseases can be improved by leveraging related phenotypes. This has motivated the development of several multi-trait PRS methods that jointly model genetically correlated traits. However, these methods do not account for vertical pleiotropy, where one trait acts as a mediator for another. Here, we introduce endoPRS, a weighted lasso model that incorporates information from relevant endophenotypes to improve disease risk prediction without making assumptions about the genetic architecture underlying the endophenotype-disease relationship. Through extensive simulation analysis, we demonstrate the robustness of endoPRS in a variety of complex genetic frameworks. We also apply endoPRS to predict the risk of childhood-onset asthma in UK Biobank and All of Us by leveraging a paired genome-wide association study of eosinophil count, a relevant endophenotype. We find that endoPRS significantly improves prediction and transferability compared to many existing PRS methods, including multi-trait PRS methods MTAG and wMT-BLUP, which suggests advantages of endoPRS in real-life clinical settings.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"39 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819159","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":"Identifying deleterious noncoding variation through gain and loss of CTCF binding activity.","authors":"Colby Tubbs, Mary Lauren Benton, Evonne McArthur, John A Capra, Douglas M Ruderfer","doi":"10.1016/j.ajhg.2025.02.009","DOIUrl":"10.1016/j.ajhg.2025.02.009","url":null,"abstract":"<p><p>CCCTC binding factor (CTCF) regulates gene expression through DNA binding at thousands of genomic loci. Genetic variation in these CTCF binding sites (CBSs) is an important driver of phenotypic variation, yet extracting those that are likely to have functional consequences in whole-genome sequencing remains challenging. To address this, we develop a hypothesis-driven framework to identify and prioritize CBS variants in gnomAD. We synthesize CTCF's binding patterns at 1,063,878 genomic loci across 214 biological contexts into a summary of binding activity. We find that high binding activity significantly correlates with both conserved nucleotides (Pearson R = 0.35, p < 2.2 × 10^-16) and sequences that contain high-quality CTCF binding motifs (Pearson R = 0.63, p = 2.9 × 10^-12). We then use binding activity to evaluate high-confidence allelic binding predictions for 1,253,329 single-nucleotide variations (SNVs) in gnomAD that disrupt a CBS. We find a strong, positive relationship between the mutability-adjusted proportion of singletons (MAPS) metric and the loss of CTCF binding at loci with high in vitro activity (Pearson R = 0.74, p < 2.2 × 10^-16). To contextualize these findings, we apply MAPS to other functional classes of variation and find that a subset of 339,380 loss of CTCF binding variants is observed as infrequently as missense variants are. This work nominates these thousands of rare, noncoding variants that disrupt CTCF binding for further functional studies while providing a blueprint for prioritizing variation in other transcription factor binding sequences.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"892-902"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571875","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":"Data-driven insights to inform splice-altering variant assessment.","authors":"Patricia J Sullivan, Julian M W Quinn, Pamela Ajuyah, Mark Pinese, Ryan L Davis, Mark J Cowley","doi":"10.1016/j.ajhg.2025.02.012","DOIUrl":"10.1016/j.ajhg.2025.02.012","url":null,"abstract":"<p><p>Disease-causing genetic variants often disrupt mRNA splicing, an intricate process that is incompletely understood. Thus, accurate inference of which genetic variants will affect splicing and what their functional consequences will be is challenging, particularly for variants outside of the essential splice sites. Here, we describe a set of data-driven heuristics that inform the interpretation of human splice-altering variants (SAVs) based on the analysis of annotated exons, experimentally validated SAVs, and the currently understood principles of splicing biology. We defined requisite splicing criteria by examining around 202,000 canonical protein-coding exons and 19,000 experimentally validated splicing branchpoints. This analysis defined the sequence, spacing, and motif strength required for splicing, with 95.9% of the exons examined meeting these criteria. By considering over 12,000 experimentally validated variants from the SpliceVarDB, we defined a set of heuristics that inform the evaluation of putative SAVs. To ensure the applicability of each heuristic, only those supported by at least 10 experimentally validated variants were considered. This allowed us to establish a measure of spliceogenicity: the proportion of variants at a location (or motif site) that affected splicing in a given context. This study makes considerable advances toward bridging the gap between computational predictions and the biological process of splicing, offering an evidence-based approach to identifying SAVs and evaluating their impact. Our splicing heuristics enhance the current framework for genetic variant evaluation with a robust, detailed, and comprehensible analysis by adding valuable context over traditional binary prediction tools.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"764-778"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584356","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":"Artificial variables help to avoid over-clustering in single-cell RNA sequencing.","authors":"Alan DenAdel, Michelle L Ramseier, Andrew W Navia, Alex K Shalek, Srivatsan Raghavan, Peter S Winter, Ava P Amini, Lorin Crawford","doi":"10.1016/j.ajhg.2025.02.014","DOIUrl":"10.1016/j.ajhg.2025.02.014","url":null,"abstract":"<p><p>Standard single-cell RNA sequencing (scRNA-seq) pipelines nearly always include unsupervised clustering as a key step in identifying biologically distinct cell types. A follow-up step in these pipelines is to test for differential expression between the identified clusters. When algorithms over-cluster, downstream analyses can produce misleading results. In this work, we present \"recall\" (calibrated clustering with artificial variables), a method for protecting against over-clustering by controlling for the impact of reusing the same data twice when performing differential expression analysis, commonly known as \"double dipping.\" Importantly, our approach can be applied to a wide range of clustering algorithms. Using real and simulated data, we show that recall provides state-of-the-art clustering performance and can rapidly analyze large-scale scRNA-seq studies, even on a personal laptop.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"940-951"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623102","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":"Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations.","authors":"Charlotte Guillouet, Valeria Agostini, Geneviève Baujat, Dario Cocciadiferro, Tommaso Pippucci, Marion Lesieur-Sebellin, Mathieu Georget, Ulrich Schatz, Christine Fauth, Raymond J Louie, Curtis Rogers, Jessica M Davis, Vassiliki Konstantopoulou, Johannes A Mayr, Arjan Bouman, Martina Wilke, Grace E VanNoy, Eleina M England, Kristen L Park, Kathleen Brown, Margarita Saenz, Antonio Novelli, Maria Cristina Digilio, Gioia Mastromoro, Mauro Ciro Antonio Rongioletti, Gerardo Piacentini, Rauan Kaiyrzhanov, Sughra Guliyeva, Lala Hasanova, Deborah Shears, Ishita Bhatnagar, Karen Stals, Oliver Klaas, Judit Horvath, Patrice Bouvagnet, P Dane Witmer, Gretchen MacCarrick, Katarina Cisarova, Jean-Marc Good, Svetlana Gorokhova, Odile Boute, Thomas Smol, Ange-Line Bruel, Olivier Patat, Julia R Broadbent, Tiong Y Tan, Natalie B Tan, Stanislas Lyonnet, Tiffany Busa, Claudio Graziano, Jeanne Amiel, Christopher T Gordon","doi":"10.1016/j.ajhg.2025.02.016","DOIUrl":"10.1016/j.ajhg.2025.02.016","url":null,"abstract":"<p><p>The Mediator complex regulates protein-coding gene transcription by coordinating the interaction of upstream enhancers with the basal transcription machinery at the promoter. Pathogenic variants in Mediator subunits typically lead to neurodevelopmental or neurodegenerative disorders with variable clinical presentations, designated as MEDopathies. Here, we report the identification of 25 individuals from 18 families with bi-allelic MED16 variants who have a multiple congenital anomalies (MCAs)-intellectual disability syndrome. Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot). Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent. The 26 variants identified were comprised of eight predicted protein-truncating (three intragenic deletions, two frameshifts, and one nonsense and two essential splice site variants) and 18 missense or in-frame duplication variants affecting conserved residues, without clear correlation between phenotypic severity and variant type combination. Three-dimensional modeling indicated that the missense and duplication variants likely have a destabilizing effect on the structural elements of the protein. Immunofluorescence assays demonstrated protein mislocalization from the nucleus to the cytoplasm for 16 of the 17 variants studied. Homozygous mutant med16 zebrafish presented growth delay and increased mortality compared with wild-type fish, and Med16 knockout mice are preweaning lethal, highlighting the conserved requirement of MED16 for development. Overall, we describe an autosomal recessive MCAs-intellectual disability MEDopathy, emphasizing the importance of Mediator during neurodevelopment and suggesting that some tissues are particularly sensitive to the loss of certain subunits.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"829-845"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623103","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":"An evolving understanding of multiple causal variants underlying genetic association signals.","authors":"Erping Long, Jacob Williams, Haoyu Zhang, Jiyeon Choi","doi":"10.1016/j.ajhg.2025.01.018","DOIUrl":"10.1016/j.ajhg.2025.01.018","url":null,"abstract":"<p><p>Understanding how genetic variation contributes to phenotypic variation is a fundamental question in genetics. Genome-wide association studies (GWASs) have discovered numerous genetic associations with various human phenotypes, most of which contain co-inherited variants in strong linkage disequilibrium (LD) with indistinguishable statistical significance. The experimental and analytical difficulty in identifying the \"causal variant\" among the co-inherited variants has traditionally led mechanistic studies to focus on relatively simple loci, where a single functional variant is presumed to explain most of the association signal and affect a target gene. The notion that a single causal variant is responsible for an association signal, while other variants in LD are merely correlated, has often been assumed in functional studies. However, emerging evidence powered by high-throughput experimental tools and context-specific functional databases argues that even a single independent signal may involve multiple functional variants in strong LD, each contributing to the observed genetic association. In this perspective, we articulate this evolving understanding of causal variants through examples from both traditional locus-by-locus approaches and more recent high-throughput functional studies. We then discuss the implications and prospects of this notion in understanding the genetic architecture of complex traits and interpreting the variant-level causality in GWAS follow-up studies.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"741-750"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447816","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":"Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis.","authors":"Evon DeBose-Scarlett, Andrew K Ressler, Carol J Gallione, Gonzalo Sapisochin Cantis, Cassi Friday, Shantel Weinsheimer, Katharina Schimmel, Edda Spiekerkoetter, Helen Kim, James R Gossage, Marie E Faughnan, Douglas A Marchuk","doi":"10.1016/j.ajhg.2025.03.007","DOIUrl":"10.1016/j.ajhg.2025.03.007","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"963"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639367","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}