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Inherited infertility: Mapping loci associated with impaired female reproduction. 遗传性不孕症:绘制与女性生殖能力受损有关的基因座图谱
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2024-12-05 Epub Date: 2024-11-19 DOI: 10.1016/j.ajhg.2024.10.018
Sanni Ruotsalainen, Juha Karjalainen, Mitja Kurki, Elisa Lahtela, Matti Pirinen, Juha Riikonen, Jarmo Ritari, Silja Tammi, Jukka Partanen, Hannele Laivuori, Aarno Palotie, Henrike Heyne, Mark Daly, Elisabeth Widen
{"title":"Inherited infertility: Mapping loci associated with impaired female reproduction.","authors":"Sanni Ruotsalainen, Juha Karjalainen, Mitja Kurki, Elisa Lahtela, Matti Pirinen, Juha Riikonen, Jarmo Ritari, Silja Tammi, Jukka Partanen, Hannele Laivuori, Aarno Palotie, Henrike Heyne, Mark Daly, Elisabeth Widen","doi":"10.1016/j.ajhg.2024.10.018","DOIUrl":"10.1016/j.ajhg.2024.10.018","url":null,"abstract":"<p><p>Female infertility is a common and complex health problem affecting millions of women worldwide. While multiple factors can contribute to this condition, the underlying cause remains elusive in up to 15%-30% of affected individuals. In our large genome-wide association study (GWAS) of 22,849 women with infertility and 198,989 control individuals from the Finnish population cohort FinnGen, we unveil a landscape of genetic factors associated with the disorder. Our recessive analysis identified a low-frequency stop-gained mutation in TATA-box binding protein-like 2 (TBPL2; c.895A>T [p.Arg299Ter]; minor-allele frequency [MAF] = 1.2%) with an impact comparable to highly penetrant monogenic mutations (odds ratio [OR] = 650, p = 4.1 × 10<sup>-25</sup>). While previous studies have linked the orthologous gene to anovulation and sterility in knockout mice, the severe consequence of the p.Arg299Ter variant was evidenced by individuals carrying two copies of that variant having significantly fewer offspring (average of 0.16) compared to women belonging to the other genotype groups (average of 1.75 offspring, p = 1.4 × 10<sup>-15</sup>). Notably, all homozygous women who had given birth had received infertility therapy. Moreover, our age-stratified analyses identified three additional genome-wide significant loci. Two loci were associated with early-onset infertility (diagnosed before age 30), located near CHEK2 and within the major histocompatibility complex (MHC) region. The third locus, associated with late-onset infertility, had its lead SNP located in an intron of a long non-coding RNA (lncRNA) gene. Taken together, our data highlight the significance of rare recessive alleles in shaping female infertility risk. The results further provide evidence supporting specific age-dependent mechanisms underlying this complex disorder.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2789-2798"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680622","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
Comparative analysis of predicted DNA secondary structures infers complex human centromere topology. 对预测的 DNA 二级结构进行比较分析,推断出复杂的人类中心粒拓扑结构。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2024-12-05 Epub Date: 2024-11-18 DOI: 10.1016/j.ajhg.2024.10.016
Sai Swaroop Chittoor, Simona Giunta
{"title":"Comparative analysis of predicted DNA secondary structures infers complex human centromere topology.","authors":"Sai Swaroop Chittoor, Simona Giunta","doi":"10.1016/j.ajhg.2024.10.016","DOIUrl":"10.1016/j.ajhg.2024.10.016","url":null,"abstract":"<p><p>Secondary structures are non-canonical arrangements of nucleic acids due to intra-strand interactions, including base pairing, stacking, or other higher-order features that deviate from the standard double-helical conformation. While these structures are extensively studied in RNA, they can also form when DNA becomes single stranded, creating topological roadblocks that can impact essential DNA-based processes such as replication, transcription, and repair, ultimately affecting genome stability. The availability of a complete linear sequence of human genomes, including repetitive loci, enables the prediction of DNA secondary structures comparing across various regions. Here, we evaluate the intrinsic properties of linear single-stranded DNA sequences derived from sampling specialized human loci such as centromeres, pericentromeres, ribosomal DNA (rDNA), and coding regions from the CHM13 genome. Our comparative analysis of predicted secondary structures across human chromosomes revealed the heightened presence, complexity, and instability of secondary structures within the centromere, which gradually decreased toward the pericentromere onto chromosomes' arms, on average lowest in coding regions. Notably, centromeric repeats exhibited the highest level of topological complexity within both the active and divergent domains, even when compared to other repetitive tandem satellites, such as rDNA in acrocentric chromosomes. Our findings provide evidence of the intrinsic self-hybridizing properties of centromere repeats, which are capable of generating complex topological structures that may functionally correlate with chromosome missegregation, especially when centromeric chromatin is disrupted. Processes such as long non-coding RNA transcription, recombination, and other mechanisms that dechromatinize and unwind stretches of linear DNA in these regions create in vivo opportunities for the DNA acrobatics hereby predicted.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2707-2719"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674906","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
Genomic medicine year in review: 2024. 基因组医学年度回顾:2024年。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2024-12-05 DOI: 10.1016/j.ajhg.2024.11.002
Teri A Manolio, Jahnavi Narula, Alauna Rupert, Carol J Bult, Rex L Chisholm, Geoffrey S Ginsburg, Eric D Green, Gillian Hooker, Gail P Jarvik, George A Mensah, Erin M Ramos, Dan M Roden, Robb Rowley, Casey Overby Taylor, Marc S Williams
{"title":"Genomic medicine year in review: 2024.","authors":"Teri A Manolio, Jahnavi Narula, Alauna Rupert, Carol J Bult, Rex L Chisholm, Geoffrey S Ginsburg, Eric D Green, Gillian Hooker, Gail P Jarvik, George A Mensah, Erin M Ramos, Dan M Roden, Robb Rowley, Casey Overby Taylor, Marc S Williams","doi":"10.1016/j.ajhg.2024.11.002","DOIUrl":"10.1016/j.ajhg.2024.11.002","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"111 12","pages":"2585-2588"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790957","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
Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection. 基于净化超选择的新生儿基因组筛查的资格预审
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2024-12-05 DOI: 10.1016/j.ajhg.2024.10.021
Stephen F Kingsmore, Meredith Wright, Laurie D Smith, Yupu Liang, William R Mowrey, Liana Protopsaltis, Matthew Bainbridge, Mei Baker, Sergey Batalov, Eric Blincow, Bryant Cao, Sara Caylor, Christina Chambers, Katarzyna Ellsworth, Annette Feigenbaum, Erwin Frise, Lucia Guidugli, Kevin P Hall, Christian Hansen, Mark Kiel, Lucita Van Der Kraan, Chad Krilow, Hugh Kwon, Lakshminarasimha Madhavrao, Sebastien Lefebvre, Jeremy Leipzig, Rebecca Mardach, Barry Moore, Danny Oh, Lauren Olsen, Eric Ontiveros, Mallory J Owen, Rebecca Reimers, Gunter Scharer, Jennifer Schleit, Seth Shelnutt, Shyamal S Mehtalia, Albert Oriol, Erica Sanford, Steve Schwartz, Kristen Wigby, Mary J Willis, Mark Yandell, Chris M Kunard, Thomas Defay
{"title":"Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection.","authors":"Stephen F Kingsmore, Meredith Wright, Laurie D Smith, Yupu Liang, William R Mowrey, Liana Protopsaltis, Matthew Bainbridge, Mei Baker, Sergey Batalov, Eric Blincow, Bryant Cao, Sara Caylor, Christina Chambers, Katarzyna Ellsworth, Annette Feigenbaum, Erwin Frise, Lucia Guidugli, Kevin P Hall, Christian Hansen, Mark Kiel, Lucita Van Der Kraan, Chad Krilow, Hugh Kwon, Lakshminarasimha Madhavrao, Sebastien Lefebvre, Jeremy Leipzig, Rebecca Mardach, Barry Moore, Danny Oh, Lauren Olsen, Eric Ontiveros, Mallory J Owen, Rebecca Reimers, Gunter Scharer, Jennifer Schleit, Seth Shelnutt, Shyamal S Mehtalia, Albert Oriol, Erica Sanford, Steve Schwartz, Kristen Wigby, Mary J Willis, Mark Yandell, Chris M Kunard, Thomas Defay","doi":"10.1016/j.ajhg.2024.10.021","DOIUrl":"10.1016/j.ajhg.2024.10.021","url":null,"abstract":"<p><p>Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs). However, a major impediment to gNBS is imprecision due to variants classified as pathogenic (P) or likely pathogenic (LP) that are not SCGD causal. gNBS with 53,855 P/LP variants, 342 genes, 412 SCGDs, and 1,603 therapies was positive in 74% of UK Biobank (UKB470K) adults, suggesting 97% false positives. We used the phenomenon of purifying hyperselection, which acts to decrease the frequency of SCGD causal diplotypes, to reduce false positives. Training of gene-disease-inheritance mode-diplotype tetrads in 618,290 control and affected subjects identified 293 variants or haplotypes and seven genes with variable inheritance contributing higher positive diplotype counts than consistent with purifying hyperselection and with little or no evidence of SCGD causality. With these changes, 2.0% of UKB470K adults were positive. In contrast, gNBS was positive in 7.2% of 3,118 critically ill children with suspected SCGDs and 7.9% of 705 infant deaths. When compared with rapid diagnostic genome sequencing (RDGS), gNBS had 99.1% recall. In eight true-positive children, gNBS was projected to decrease time to diagnosis by a median of 121 days and avoid life-threatening disease presentations in four children, organ damage in six children, ∼$1.25 million in healthcare cost, and ten (1.4%) infant deaths. Federated training predicated on purifying hyperselection provides a general framework to attain high precision in population screening. Federated training across many biobanks and clinical trials can provide a privacy-preserving mechanism for qualification of gNBS in diverse genetic ancestries.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"111 12","pages":"2618-2642"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790961","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
GPS-Net: Discovering prognostic pathway modules based on network regularized kernel learning. GPS-Net:基于网络正则化核学习发现预后路径模块
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2024-12-05 Epub Date: 2024-11-06 DOI: 10.1016/j.ajhg.2024.10.004
Sijie Yao, Kaiqiao Li, Tingyi Li, Xiaoqing Yu, Pei Fen Kuan, Xuefeng Wang
{"title":"GPS-Net: Discovering prognostic pathway modules based on network regularized kernel learning.","authors":"Sijie Yao, Kaiqiao Li, Tingyi Li, Xiaoqing Yu, Pei Fen Kuan, Xuefeng Wang","doi":"10.1016/j.ajhg.2024.10.004","DOIUrl":"10.1016/j.ajhg.2024.10.004","url":null,"abstract":"<p><p>The search for prognostic biomarkers capable of predicting patient outcomes, by analyzing gene expression in tissue samples and other molecular profiles, remains largely focused on single-gene-based or global-gene-search approaches. Gene-centric approaches, while foundational, fail to capture the higher-order dependencies that reflect the activities of co-regulated processes, pathway alterations, and regulatory networks, all of which are crucial in determining the patient outcomes in complex diseases like cancer. Here, we introduce GPS-Net, a computational framework that fills the gap in efficiently identifying prognostic modules by incorporating the holistic pathway structures and the network of gene interactions. By innovatively incorporating advanced multiple kernel learning techniques and network-based regularization, the proposed method not only enhances the accuracy of biomarker and pathway identification but also significantly reduces computational complexity, as demonstrated by extensive simulation studies. Applying GPS-Net, we identified key pathways that are predictive of patient outcomes in a cancer immunotherapy study. Overall, our approach provides a novel framework that renders genome-wide pathway-level prognostic analysis both feasible and scalable, synergizing both mechanism-driven and data-driven methodologies for precision genomics.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2826-2838"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602781","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
Local genetic correlation via knockoffs reduces confounding due to cross-trait assortative mating. 通过 "山寨 "产生的局部遗传相关性减少了跨性状同配所造成的混杂。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2024-12-05 Epub Date: 2024-11-14 DOI: 10.1016/j.ajhg.2024.10.012
Shiyang Ma, Fan Wang, Richard Border, Joseph Buxbaum, Noah Zaitlen, Iuliana Ionita-Laza
{"title":"Local genetic correlation via knockoffs reduces confounding due to cross-trait assortative mating.","authors":"Shiyang Ma, Fan Wang, Richard Border, Joseph Buxbaum, Noah Zaitlen, Iuliana Ionita-Laza","doi":"10.1016/j.ajhg.2024.10.012","DOIUrl":"10.1016/j.ajhg.2024.10.012","url":null,"abstract":"<p><p>Local genetic correlation analysis is an important tool for identifying genetic loci with shared biology across traits. Recently, Border et al. have shown that the results of these analyses are confounded by cross-trait assortative mating (xAM), leading to many false-positive findings. Here, we describe LAVA-Knock, a local genetic correlation method that builds off an existing genetic correlation method, LAVA, and augments it by generating synthetic data in a way that preserves local and long-range linkage disequilibrium (LD), allowing us to reduce the confounding induced by xAM. We show in simulations based on a realistic xAM model and in genome-wide association study (GWAS) applications for 630 trait pairs that LAVA-Knock can greatly reduce the bias due to xAM relative to LAVA. Furthermore, we show a significant positive correlation between the reduction in local genetic correlations and estimates in the literature of cross-mate phenotype correlations; in particular, pairs of traits that are known to have high cross-mate phenotype correlation values have a significantly higher reduction in the number of local genetic correlations compared with other trait pairs. A few representative examples include education and intelligence, education and alcohol consumption, and attention-deficit hyperactivity disorder and depression. These results suggest that LAVA-Knock can reduce confounding due to both short-range LD and long-range LD induced by xAM.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2839-2848"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638545","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
Employing effective recruitment and retention strategies to engage a diverse pediatric population in genomics research. 采用有效的招聘和留用策略,让多样化的儿科人群参与基因组学研究。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2024-12-05 Epub Date: 2024-11-19 DOI: 10.1016/j.ajhg.2024.10.015
Michelle A Ramos, Katherine E Bonini, Laura Scarimbolo, Nicole R Kelly, Beverly Insel, Sabrina A Suckiel, Kaitlyn Brown, Miranda Di Biase, Katie M Gallagher, Jessenia Lopez, Karla López Aguiñiga, Priya N Marathe, Estefany Maria, Jacqueline A Odgis, Jessica E Rodriguez, Michelle A Rodriguez, Nairovylex Ruiz, Monisha Sebastin, Nicole M Yelton, Charlotte Cunningham-Rundles, Melvin Gertner, Irma Laguerre, Thomas V McDonald, Patricia E McGoldrick, Mimsie Robinson, Arye Rubinstein, Lisa H Shulman, Trinisha Williams, Steven M Wolf, Elissa G Yozawitz, Randi E Zinberg, Noura S Abul-Husn, Laurie J Bauman, George A Diaz, Bart S Ferket, John M Greally, Vaidehi Jobanputra, Bruce D Gelb, Eimear E Kenny, Melissa P Wasserstein, Carol R Horowitz
{"title":"Employing effective recruitment and retention strategies to engage a diverse pediatric population in genomics research.","authors":"Michelle A Ramos, Katherine E Bonini, Laura Scarimbolo, Nicole R Kelly, Beverly Insel, Sabrina A Suckiel, Kaitlyn Brown, Miranda Di Biase, Katie M Gallagher, Jessenia Lopez, Karla López Aguiñiga, Priya N Marathe, Estefany Maria, Jacqueline A Odgis, Jessica E Rodriguez, Michelle A Rodriguez, Nairovylex Ruiz, Monisha Sebastin, Nicole M Yelton, Charlotte Cunningham-Rundles, Melvin Gertner, Irma Laguerre, Thomas V McDonald, Patricia E McGoldrick, Mimsie Robinson, Arye Rubinstein, Lisa H Shulman, Trinisha Williams, Steven M Wolf, Elissa G Yozawitz, Randi E Zinberg, Noura S Abul-Husn, Laurie J Bauman, George A Diaz, Bart S Ferket, John M Greally, Vaidehi Jobanputra, Bruce D Gelb, Eimear E Kenny, Melissa P Wasserstein, Carol R Horowitz","doi":"10.1016/j.ajhg.2024.10.015","DOIUrl":"10.1016/j.ajhg.2024.10.015","url":null,"abstract":"<p><p>Underrepresentation in clinical genomics research limits the generalizability of findings and the benefits of scientific discoveries. We describe the impact of patient-centered, data-driven recruitment and retention strategies in a pediatric genome sequencing study. We collaborated with a stakeholder board, conducted formative research with adults whose children had undergone genomic testing, and piloted and revised study approaches and materials. Our approaches included racially, ethnically, and linguistically congruent study staff, relational interactions, study visit flexibility, and data-informed quality improvement. Of 1,656 eligible children, only 6.5% declined. Their parents/legal guardians were 76.9% non-White, 65.6% had public health insurance for the child, 49.9% lived below the federal poverty level, and 52.8% resided in a medically underserved area. Among those enrolled, 87.3% completed all study procedures. There were no sociodemographic differences between those who enrolled and declined or between those retained and lost to follow-up. We outline stakeholder-engaged approaches that may have led to the successful enrollment and retention of diverse families. These approaches may inform future research initiatives aiming to engage and retain underrepresented populations in genomics medicine research.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2607-2617"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680668","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
Profiling genetically driven alternative splicing across the Indonesian archipelago. 剖析印度尼西亚群岛的基因驱动替代剪接。
IF 5.4 1区 生物学
American journal of human genetics Pub Date : 2024-11-07 Epub Date: 2024-10-08 DOI: 10.1016/j.ajhg.2024.09.004
Neke Ibeh, Pradiptajati Kusuma, Chelzie Crenna Darusallam, Safarina G Malik, Herawati Sudoyo, Davis J McCarthy, Irene Gallego Romero
{"title":"Profiling genetically driven alternative splicing across the Indonesian archipelago.","authors":"Neke Ibeh, Pradiptajati Kusuma, Chelzie Crenna Darusallam, Safarina G Malik, Herawati Sudoyo, Davis J McCarthy, Irene Gallego Romero","doi":"10.1016/j.ajhg.2024.09.004","DOIUrl":"10.1016/j.ajhg.2024.09.004","url":null,"abstract":"<p><p>One of the regulatory mechanisms influencing the functional capacity of genes is alternative splicing (AS). Previous studies exploring the splicing landscape of human tissues have shown that AS has contributed to human biology, especially in disease progression and the immune response. Nonetheless, this phenomenon remains poorly characterized across human populations, and it is unclear how genetic and environmental variation contribute to AS. Here, we examine a set of 115 Indonesian samples from three traditional island populations spanning the genetic ancestry cline that characterizes Island Southeast Asia. We conduct a global AS analysis between islands to ascertain the degree of functionally significant AS events and their consequences. Using an event-based statistical model, we detected over 1,500 significant differential AS events across all comparisons. Additionally, we identify over 6,000 genetic variants associated with changes in splicing (splicing quantitative trait loci [sQTLs]), some of which are driven by Papuan-like genetic ancestry, and only show partial overlap with other publicly available sQTL datasets derived from other populations. Computational predictions of RNA binding activity reveal that a fraction of these sQTLs directly modulate the binding propensity of proteins involved in the splicing regulation of immune genes. Overall, these results contribute toward elucidating the role of genetic variation in shaping gene regulation in one of the most diverse regions in the world.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2458-2477"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387312","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
Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs. 厘清近端 16p11.2 BP4-5 CNV 多效应背后的机制。
IF 5.4 1区 生物学
American journal of human genetics Pub Date : 2024-11-07 Epub Date: 2024-09-26 DOI: 10.1016/j.ajhg.2024.08.014
Chiara Auwerx, Samuel Moix, Zoltán Kutalik, Alexandre Reymond
{"title":"Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs.","authors":"Chiara Auwerx, Samuel Moix, Zoltán Kutalik, Alexandre Reymond","doi":"10.1016/j.ajhg.2024.08.014","DOIUrl":"10.1016/j.ajhg.2024.08.014","url":null,"abstract":"<p><p>Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carrier individuals among unrelated White British UK Biobank participants, we performed a phenome-wide association study (PheWAS) between the region's copy number and 117 complex traits and diseases, mimicking four dosage models. Forty-six phenotypes (39%) were affected by 16p11.2 BP4-5 CNVs, with the deletion-only, mirror, U-shape, and duplication-only models being the best fit for 30, 10, 4, and 2 phenotypes, respectively, aligning with the stronger deleteriousness of the deletion. Upon individually adjusting CNV effects for either body mass index (BMI), height, or educational attainment (EA), we found that sixteen testable deletion-driven associations-primarily with cardiovascular and metabolic traits-were BMI dependent, with EA playing a more subtle role and no association depending on height. Bidirectional Mendelian randomization supported that 13 out of these 16 associations were secondary consequences of the CNV's impact on BMI. For the 23 traits that remained significantly associated upon individual adjustment for mediators, matched-control analyses found that 10 phenotypes, including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, and pneumonia and acute kidney injury risk, remained associated under strict Bonferroni correction, with 10 additional nominally significant associations. These results paint a complex picture of 16p11.2 BP4-5's pleiotropic pattern that involves direct effects on multiple physiological systems and indirect co-morbidities consequential to the CNV's impact on BMI and EA, acting through trait-specific dosage mechanisms.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2347-2361"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339424","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
Inverse relationship between polygenic risk burden and age of onset of autoimmune vitiligo. 多基因风险负担与自身免疫性白癜风发病年龄之间的反比关系。
IF 5.4 1区 生物学
American journal of human genetics Pub Date : 2024-11-07 Epub Date: 2024-10-16 DOI: 10.1016/j.ajhg.2024.09.007
Genevieve H L Roberts, Pamela R Fain, Stephanie A Santorico, Richard A Spritz
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