American journal of human genetics最新文献_第10页

Exploring the noncoding genome with chromosomal structural rearrangements. 利用染色体结构重排探索非编码基因组

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2024-07-11 DOI: 10.1016/j.ajhg.2024.05.010

Cynthia Casson Morton

引用次数: 0

Evaluation of polygenic scoring methods in five biobanks shows larger variation between biobanks than methods and finds benefits of ensemble learning. 在五个生物库中对多基因评分方法进行的评估显示，生物库之间的差异大于方法之间的差异，并发现了集合学习的优势。

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2024-07-11 Epub Date: 2024-06-21 DOI: 10.1016/j.ajhg.2024.06.003

Remo Monti, Lisa Eick, Georgi Hudjashov, Kristi Läll, Stavroula Kanoni, Brooke N Wolford, Benjamin Wingfield, Oliver Pain, Sophie Wharrie, Bradley Jermy, Aoife McMahon, Tuomo Hartonen, Henrike Heyne, Nina Mars, Samuel Lambert, Kristian Hveem, Michael Inouye, David A van Heel, Reedik Mägi, Pekka Marttinen, Samuli Ripatti, Andrea Ganna, Christoph Lippert

{"title":"Evaluation of polygenic scoring methods in five biobanks shows larger variation between biobanks than methods and finds benefits of ensemble learning.","authors":"Remo Monti, Lisa Eick, Georgi Hudjashov, Kristi Läll, Stavroula Kanoni, Brooke N Wolford, Benjamin Wingfield, Oliver Pain, Sophie Wharrie, Bradley Jermy, Aoife McMahon, Tuomo Hartonen, Henrike Heyne, Nina Mars, Samuel Lambert, Kristian Hveem, Michael Inouye, David A van Heel, Reedik Mägi, Pekka Marttinen, Samuli Ripatti, Andrea Ganna, Christoph Lippert","doi":"10.1016/j.ajhg.2024.06.003","DOIUrl":"10.1016/j.ajhg.2024.06.003","url":null,"abstract":"Methods of estimating polygenic scores (PGSs) from genome-wide association studies are increasingly utilized. However, independent method evaluation is lacking, and method comparisons are often limited. Here, we evaluate polygenic scores derived via seven methods in five biobank studies (totaling about 1.2 million participants) across 16 diseases and quantitative traits, building on a reference-standardized framework. We conducted meta-analyses to quantify the effects of method choice, hyperparameter tuning, method ensembling, and the target biobank on PGS performance. We found that no single method consistently outperformed all others. PGS effect sizes were more variable between biobanks than between methods within biobanks when methods were well tuned. Differences between methods were largest for the two investigated autoimmune diseases, seropositive rheumatoid arthritis and type 1 diabetes. For most methods, cross-validation was more reliable for tuning hyperparameters than automatic tuning (without the use of target data). For a given target phenotype, elastic net models combining PGS across methods (ensemble PGS) tuned in the UK Biobank provided consistent, high, and cross-biobank transferable performance, increasing PGS effect sizes (β coefficients) by a median of 5.0% relative to LDpred2 and MegaPRS (the two best-performing single methods when tuned with cross-validation). Our interactively browsable online-results and open-source workflow prspipe provide a rich resource and reference for the analysis of polygenic scoring methods across biobanks.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1431-1447"},"PeriodicalIF":8.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141439990","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}

引用次数: 0

GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas. GNA14 和 GNAQ 体细胞突变会导致脊柱和颅内轴外海绵状血管瘤。

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2024-07-11 Epub Date: 2024-06-24 DOI: 10.1016/j.ajhg.2024.05.020

Jian Ren, Ziwei Cui, Chendan Jiang, Leiming Wang, Yunqian Guan, Yeqing Ren, Shikun Zhang, Tianqi Tu, Jiaxing Yu, Ye Li, Wanru Duan, Jian Guan, Kai Wang, Hongdian Zhang, Dong Xing, Mark L Kahn, Hongqi Zhang, Tao Hong

{"title":"GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas.","authors":"Jian Ren, Ziwei Cui, Chendan Jiang, Leiming Wang, Yunqian Guan, Yeqing Ren, Shikun Zhang, Tianqi Tu, Jiaxing Yu, Ye Li, Wanru Duan, Jian Guan, Kai Wang, Hongdian Zhang, Dong Xing, Mark L Kahn, Hongqi Zhang, Tao Hong","doi":"10.1016/j.ajhg.2024.05.020","DOIUrl":"10.1016/j.ajhg.2024.05.020","url":null,"abstract":"Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored downstream signaling pathways, gene expression changes, and resultant phenotypic shifts induced by these mutations, both in vitro and in vivo. In our cohort, 77.4% of samples had somatic missense variants in GNA14, GNAQ, or GJA4. Transcriptomic analysis highlighted significant pathway upregulation, with the GNAQ c.626A>G (p.Gln209Arg) mutation elevating PI3K-AKT-mTOR and angiogenesis-related pathways, while GNA14 c.614A>T (p.Gln205Leu) mutation led to MAPK and angiogenesis-related pathway upregulation. Using a mouse xenograft model, we observed enlarged vessels from these mutations. Additionally, we initiated rapamycin treatment in a 14-year-old individual harboring the GNAQ c.626A>G (p.Gln209Arg) variant, resulting in gradual regression of cutaneous cavernous hemangiomas and improved motor strength, with minimal side effects. Understanding these mutations and their pathways provides a foundation for developing therapies for ECHs resistant to current therapies. Indeed, the administration of rapamycin in an individual within this study highlights the promise of targeted treatments in treating these complex lesions.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1370-1382"},"PeriodicalIF":8.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449416","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}

引用次数: 0

The 2023 Distinguished Speakers Symposium: Closing Remarks. 2023 年杰出演讲人研讨会：闭幕词。

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2024-07-11 DOI: 10.1016/j.ajhg.2024.05.009

Ambroise Wonkam

引用次数: 0

KnockoffHybrid: A knockoff framework for hybrid analysis of trio and population designs in genome-wide association studies. KnockoffHybrid：用于对全基因组关联研究中的三人设计和群体设计进行混合分析的混合框架。

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2024-07-11 Epub Date: 2024-05-30 DOI: 10.1016/j.ajhg.2024.05.003

Yi Yang, Qi Wang, Chen Wang, Joseph Buxbaum, Iuliana Ionita-Laza

{"title":"KnockoffHybrid: A knockoff framework for hybrid analysis of trio and population designs in genome-wide association studies.","authors":"Yi Yang, Qi Wang, Chen Wang, Joseph Buxbaum, Iuliana Ionita-Laza","doi":"10.1016/j.ajhg.2024.05.003","DOIUrl":"10.1016/j.ajhg.2024.05.003","url":null,"abstract":"Both trio and population designs are popular study designs for identifying risk genetic variants in genome-wide association studies (GWASs). The trio design, as a family-based design, is robust to confounding due to population structure, whereas the population design is often more powerful due to larger sample sizes. Here, we propose KnockoffHybrid, a knockoff-based statistical method for hybrid analysis of both the trio and population designs. KnockoffHybrid provides a unified framework that brings together the advantages of both designs and produces powerful hybrid analysis while controlling the false discovery rate (FDR) in the presence of linkage disequilibrium and population structure. Furthermore, KnockoffHybrid has the flexibility to leverage different types of summary statistics for hybrid analyses, including expression quantitative trait loci (eQTL) and GWAS summary statistics. We demonstrate in simulations that KnockoffHybrid offers power gains over non-hybrid methods for the trio and population designs with the same number of cases while controlling the FDR with complex correlation among variants and population structure among subjects. In hybrid analyses of three trio cohorts for autism spectrum disorders (ASDs) from the Autism Speaks MSSNG, Autism Sequencing Consortium, and Autism Genome Project with GWAS summary statistics from the iPSYCH project and eQTL summary statistics from the MetaBrain project, KnockoffHybrid outperforms conventional methods by replicating several known risk genes for ASDs and identifying additional associations with variants in other genes, including the PRAME family genes involved in axon guidance and which may act as common targets for human speech/language evolution and related disorders.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1448-1461"},"PeriodicalIF":8.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183463","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}

引用次数: 0

Impact of genome build on RNA-seq interpretation and diagnostics. 基因组构建对 RNA-seq 解释和诊断的影响。

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2024-07-11 Epub Date: 2024-06-03 DOI: 10.1016/j.ajhg.2024.05.005

Rachel A Ungar, Pagé C Goddard, Tanner D Jensen, Fabien Degalez, Kevin S Smith, Christopher A Jin, Devon E Bonner, Jonathan A Bernstein, Matthew T Wheeler, Stephen B Montgomery

{"title":"Impact of genome build on RNA-seq interpretation and diagnostics.","authors":"Rachel A Ungar, Pagé C Goddard, Tanner D Jensen, Fabien Degalez, Kevin S Smith, Christopher A Jin, Devon E Bonner, Jonathan A Bernstein, Matthew T Wheeler, Stephen B Montgomery","doi":"10.1016/j.ajhg.2024.05.005","DOIUrl":"10.1016/j.ajhg.2024.05.005","url":null,"abstract":"Transcriptomics is a powerful tool for unraveling the molecular effects of genetic variants and disease diagnosis. Prior studies have demonstrated that choice of genome build impacts variant interpretation and diagnostic yield for genomic analyses. To identify the extent genome build also impacts transcriptomics analyses, we studied the effect of the hg19, hg38, and CHM13 genome builds on expression quantification and outlier detection in 386 rare disease and familial control samples from both the Undiagnosed Diseases Network and Genomics Research to Elucidate the Genetics of Rare Disease Consortium. Across six routinely collected biospecimens, 61% of quantified genes were not influenced by genome build. However, we identified 1,492 genes with build-dependent quantification, 3,377 genes with build-exclusive expression, and 9,077 genes with annotation-specific expression across six routinely collected biospecimens, including 566 clinically relevant and 512 known OMIM genes. Further, we demonstrate that between builds for a given gene, a larger difference in quantification is well correlated with a larger change in expression outlier calling. Combined, we provide a database of genes impacted by build choice and recommend that transcriptomics-guided analyses and diagnoses are cross referenced with these data for robustness.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1282-1300"},"PeriodicalIF":8.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247052","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}

引用次数: 0

Identification and correction for collider bias in a genome-wide association study of diabetes-related heart failure. 糖尿病相关心力衰竭全基因组关联研究中对撞机偏差的识别与校正。

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2024-07-11 Epub Date: 2024-06-18 DOI: 10.1016/j.ajhg.2024.05.018

Yan V Sun, Chang Liu, Qin Hui, Jin J Zhou, J Michael Gaziano, Peter W F Wilson, Jacob Joseph, Lawrence S Phillips

{"title":"Identification and correction for collider bias in a genome-wide association study of diabetes-related heart failure.","authors":"Yan V Sun, Chang Liu, Qin Hui, Jin J Zhou, J Michael Gaziano, Peter W F Wilson, Jacob Joseph, Lawrence S Phillips","doi":"10.1016/j.ajhg.2024.05.018","DOIUrl":"10.1016/j.ajhg.2024.05.018","url":null,"abstract":"Type 2 diabetes (T2D) is a major risk factor for heart failure (HF) and has elevated incidence among individuals with HF. Since genetics and HF can independently influence T2D, collider bias may occur when T2D (i.e., collider) is controlled for by design or analysis. Thus, we conducted a genome-wide association study (GWAS) of diabetes-related HF with correction for collider bias. We first performed a GWAS of HF to identify genetic instrumental variables (GIVs) for HF and to enable bidirectional Mendelian randomization (MR) analysis between T2D and HF. We identified 61 genomic loci, significantly associated with all-cause HF in 114,275 individuals with HF and over 1.5 million controls of European ancestry. Using a two-sample bidirectional MR approach with 59 and 82 GIVs for HF and T2D, respectively, we estimated that T2D increased HF risk (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.10), while HF also increased T2D risk (OR 1.60, 95% CI 1.36-1.88). Then we performed a GWAS of diabetes-related HF corrected for collider bias due to the study design of index cases. After removing the spurious association of TCF7L2 locus due to collider bias, we identified two genome-wide significant loci close to PITX2 (chromosome 4) and CDKN2B-AS1 (chromosome 9) associated with diabetes-related HF in the Million Veteran Program and replicated the associations in the UK Biobank. Our MR findings provide strong evidence that HF increases T2D risk. As a result, collider bias leads to spurious genetic associations of diabetes-related HF, which can be effectively corrected to identify true positive loci.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1481-1493"},"PeriodicalIF":8.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426138","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}

引用次数: 0

Truncated variants of MAGEL2 are involved in the etiologies of the Schaaf-Yang and Prader-Willi syndromes. MAGEL2的截短变体与Schaaf-Yang综合征和Prader-Willi综合征的病因有关。

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2024-07-11 Epub Date: 2024-06-21 DOI: 10.1016/j.ajhg.2024.05.023

David Heimdörfer, Alexander Vorleuter, Alexander Eschlböck, Angeliki Spathopoulou, Marta Suarez-Cubero, Hesso Farhan, Veronika Reiterer, Melanie Spanjaard, Christian P Schaaf, Lukas A Huber, Leopold Kremser, Bettina Sarg, Frank Edenhofer, Stephan Geley, Mariana E G de Araujo, Alexander Huettenhofer

{"title":"Truncated variants of MAGEL2 are involved in the etiologies of the Schaaf-Yang and Prader-Willi syndromes.","authors":"David Heimdörfer, Alexander Vorleuter, Alexander Eschlböck, Angeliki Spathopoulou, Marta Suarez-Cubero, Hesso Farhan, Veronika Reiterer, Melanie Spanjaard, Christian P Schaaf, Lukas A Huber, Leopold Kremser, Bettina Sarg, Frank Edenhofer, Stephan Geley, Mariana E G de Araujo, Alexander Huettenhofer","doi":"10.1016/j.ajhg.2024.05.023","DOIUrl":"10.1016/j.ajhg.2024.05.023","url":null,"abstract":"The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11-q13. A deletion of the SNORD116 cluster, encoding small nucleolar RNAs, or frameshift mutations within MAGEL2 result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that in contrast to a predominant cytoplasmic localization of wild-type (WT) MAGEL2, a truncated MAGEL2 mutant was evenly distributed between the cytoplasm and the nucleus. To elucidate regulatory pathways that may underlie both diseases, we identified protein interaction partners for WT or mutant MAGEL2, in particular the survival motor neuron protein (SMN), involved in spinal muscular atrophy, and the fragile-X-messenger ribonucleoprotein (FMRP), involved in autism spectrum disorders. The interactome of the non-coding RNA SNORD116 was also investigated by RNA-CoIP. We show that WT and truncated MAGEL2 were both involved in RNA metabolism, while regulation of transcription was mainly observed for WT MAGEL2. Hence, we investigated the influence of MAGEL2 mutations on the expression of genes from the PWS locus, including the SNORD116 cluster. Thereby, we provide evidence for MAGEL2 mutants decreasing the expression of SNORD116, SNORD115, and SNORD109A, as well as protein-coding genes MKRN3 and SNRPN, thus bridging the gap between PWS and SYS.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1383-1404"},"PeriodicalIF":8.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141439991","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}

引用次数: 0

The 2023 Distinguished Speakers Symposium: The future of human genetics and genomics. 2023 年杰出演讲者研讨会：人类遗传学和基因组学的未来。

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2024-07-11 DOI: 10.1016/j.ajhg.2024.05.008

Huntington F Willard

引用次数: 0

The DARC side of genetics in cancer: Breast cancer disparities. 癌症遗传学的 DARC 方面：乳腺癌的差异。

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2024-07-11 DOI: 10.1016/j.ajhg.2024.05.011

Rachel Martini, Melissa B Davis

引用次数: 0