المؤلفون: Schierenbeck, Matías, Alqudah, Ahmad Mohammad, Thabet, Samar Gamal, Avogadro, Evangelina Gabriela, Dietz, Juan Ignacio, Simón, María Rosa, Börner, Andreas

المصدر: Scientific Reports 14 : Article number: 13316 (June 2024)

مصطلحات موضوعية: Hoja Bandera, Trigo, Heterogeneidad Alélica, Genes Candidatos, Variación Fenotípica, Flag Leaf, Wheat, Allelic Heterogeneity, Candidate Genes, Phenotypic Variation

الوصف: Flag leaf (FL) dimension has been reported as a key ecophysiological aspect for boosting grain yield in wheat. A worldwide winter wheat panel consisting of 261 accessions was tested to examine the phenotypical variation and identify quantitative trait nucleotides (QTNs) with candidate genes influencing FL morphology. To this end, four FL traits were evaluated during the early milk stage under two growing seasons at the Leibniz Institute of Plant Genetics and Crop Plant Research. The results showed that all leaf traits (Flag leaf length, width, area, and length/width ratio) were significantly influenced by the environments, genotypes, and environments × genotypes interactions. Then, a genome-wide association analysis was performed using 17,093 SNPs that showed 10 novel QTNs that potentially play a role in modulating FL morphology in at least two environments. Further analysis revealed 8 high-confidence candidate genes likely involved in these traits and showing high expression values from flag leaf expansion until its senescence and also during grain development. An important QTN (wsnp_RFL_Contig2177_1500201) was associated with FL width and located inside TraesCS3B02G047300 at chromosome 3B. This gene encodes a major facilitator, sugar transporter-like, and showed the highest expression values among the candidate genes reported, suggesting their positive role in controlling flag leaf and potentially being involved in photosynthetic assimilation. Our study suggests that the detection of novel marker-trait associations and the subsequent elucidation of the genetic mechanism influencing FL morphology would be of interest for improving plant architecture, light capture, and photosynthetic efficiency during grain development. ; EEA Bordenave ; Fil: Schierenbeck, Matías. Leibniz Institute of Plant Genetics and Crop Plant Research (IPK). Genebank Department; Alemania ; Fil: Schierenbeck, Matías. Universidad Nacional de La Plata. Facultad de Ciencias Agrarias y Forestales; Argentina ; Fil: Schierenbeck, Matías. Consejo ...

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/20.500.12123/18360Test; https://www.nature.com/articles/s41598-024-64161-xTest; https://doi.org/10.1038/s41598-024-64161-xTest

الإتاحة: https://doi.org/20.500.12123/1836010.1038/s41598-024-64161-xTest
https://hdl.handle.net/20.500.12123/18360Test
https://www.nature.com/articles/s41598-024-64161-xTest

المؤلفون: Beecham, AH, Amezcua, L, Chinea, A, Manrique, CP, Rubi, C, Isobe, N, Lund, BT, Santaniello, A, Beecham, GW, Burchard, EG, Comabella, M, Patsopoulos, N, Fitzgerald, K, Calabresi, PA, De Jager, P, Conti, DV, Delgado, SR, Oksenberg, JR, McCauley, JL

المصدر: Multiple sclerosis (Houndmills, Basingstoke, England). 26(11)

مصطلحات موضوعية: Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide, Alleles, United States, Genetic Variation, Hispanic or Latino, Black or African American, Multiple sclerosis, admixture, allelic heterogeneity, genetics, locus heterogeneity, multi-ethnic, pathway analysis, risk score, Genetics, Neurodegenerative, Human Genome, Brain Disorders, Clinical Research, Autoimmune Disease, Genetic Testing, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Clinical Sciences, Neurology & Neurosurgery

الوصف: BackgroundSubstantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States.ObjectiveWe sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex (n = 200) within these populations.MethodsGenotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses.ResultsWe found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene-environment or gene-gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability.ConclusionThese findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/495927p3Test

المؤلفون: Willems, Emileigh L, Wan, Jia Y, Norden-Krichmar, Trina M, Edwards, Karen L, Santorico, Stephanie A

المصدر: Genetic epidemiology. 44(1)

مصطلحات موضوعية: Humans, Diabetes Mellitus, Type 2, Phenotype, Polymorphism, Single Nucleotide, Mexican Americans, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Metabolic Syndrome, White People, Black or African American, Asian, allelic heterogeneity, genome-wide association, meta-analysis, metabolic syndrome, transethnic, Human Genome, Diabetes, Genetics, Nutrition, Metabolic and endocrine, African Americans, Asian Americans, Whites, Public Health and Health Services, Epidemiology

الوصف: Genome-wide association studies (GWAS) have been used to establish thousands of genetic associations across numerous phenotypes. To improve the power of GWAS and generalize associations across ethnic groups, transethnic meta-analysis methods are used to combine the results of several GWAS from diverse ancestries. The goal of this study is to identify genetic associations for eight quantitative metabolic syndrome (MetS) traits through a meta-analysis across four ethnic groups. Traits were measured in the GENetics of Noninsulin dependent Diabetes Mellitus (GENNID) Study which consists of African-American (families = 73, individuals = 288), European-American (families = 79, individuals = 519), Japanese-American (families = 17, individuals = 132), and Mexican-American (families = 113, individuals = 610) samples. Genome-wide association results from these four ethnic groups were combined using four meta-analysis methods: fixed effects, random effects, TransMeta, and MR-MEGA. We provide an empirical comparison of the four meta-analysis methods from the GENNID results, discuss which types of loci (characterized by allelic heterogeneity) appear to be better detected by each of the four meta-analysis methods in the GENNID Study, and validate our results using previous genetic discoveries. We specifically compare the two transethnic methods, TransMeta and MR-MEGA, and discuss how each transethnic method's framework relates to the types of loci best detected by each method.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/10p123ccTest

المؤلفون: Emmanuelle Masson, Wen-Bin Zou, Emmanuelle Génin, David N. Cooper, Gerald Le Gac, Yann Fichou, Na Pu, Vinciane Rebours, Claude Férec, Zhuan Liao, Jian-Min Chen

المصدر: Human Genomics, Vol 16, Iss 1, Pp 1-15 (2022)

مصطلحات موضوعية: ACMG guidelines, Allele frequency threshold, Allelic heterogeneity, Disease prevalence, Exome sequencing, Genetic heterogeneity, Medicine, Genetics, QH426-470

الوصف: Abstract Background The American College of Medical Genetics and Genomics (ACMG)-recommended five variant classification categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign) have been widely used in medical genetics. However, these guidelines are fundamentally constrained in practice owing to their focus upon Mendelian disease genes and their dichotomous classification of variants as being either causal or not. Herein, we attempt to expand the ACMG guidelines into a general variant classification framework that takes into account not only the continuum of clinical phenotypes, but also the continuum of the variants’ genetic effects, and the different pathological roles of the implicated genes. Main body As a disease model, we employed chronic pancreatitis (CP), which manifests clinically as a spectrum from monogenic to multifactorial. Bearing in mind that any general conceptual proposal should be based upon sound data, we focused our analysis on the four most extensively studied CP genes, PRSS1, CFTR, SPINK1 and CTRC. Based upon several cross-gene and cross-variant comparisons, we first assigned the different genes to two distinct categories in terms of disease causation: CP-causing (PRSS1 and SPINK1) and CP-predisposing (CFTR and CTRC). We then employed two new classificatory categories, “predisposing” and “likely predisposing”, to replace ACMG’s “pathogenic” and “likely pathogenic” categories in the context of CP-predisposing genes, thereby classifying all pathologically relevant variants in these genes as “predisposing”. In the case of CP-causing genes, the two new classificatory categories served to extend the five ACMG categories whilst two thresholds (allele frequency and functional) were introduced to discriminate “pathogenic” from “predisposing” variants. Conclusion Employing CP as a disease model, we expand ACMG guidelines into a five-category classification system (predisposing, likely predisposing, uncertain significance, likely benign, and benign) and a seven-category classification system (pathogenic, likely pathogenic, predisposing, likely predisposing, uncertain significance, likely benign, and benign) in the context of disease-predisposing and disease-causing genes, respectively. Taken together, the two systems constitute a general variant classification framework that, in principle, should span the entire spectrum of variants in any disease-related gene. The maximal compliance of our five-category and seven-category classification systems with the ACMG guidelines ought to facilitate their practical application.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1479-7364Test

الوصول الحر: https://doaj.org/article/2eb0e4b3e2f04a0db191e0fc90b873c0Test

المؤلفون: Sheng‐Jia Lin, Barbara Vona, Tracy Lau, Kevin Huang, Maha S. Zaki, Huda Shujaa Aldeen, Ehsan Ghayoor Karimiani, Clarissa Rocca, Mahmoud M. Noureldeen, Ahmed K. Saad, Cassidy Petree, Tobias Bartolomaeus, Rami Abou Jamra, Giovanni Zifarelli, Aditi Gotkhindikar, Ingrid M. Wentzensen, Min Liao, Emalyn Cork, Pratishtha Varshney, Narges Hashemi, Mohammad Hasan Mohammadi, Abolfazl Rad, Juanita Neira, Mehran Beiraghi Toosi, Cordula Knopp, Ingo Kurth, Thomas D. Challman, Rebecca Smith, Asmahan Abdalla, Thomas Haaf, Mohnish Suri, M. P. Joshi, Wendy K. Chung, Andres Moreno‐De‐Luca, Henry Houlden, Reza Maroofian, Gaurav K. Varshney

مصطلحات موضوعية: Standards and Guidelines for Genetic Variant Interpretation, Genetics, FOS Biological sciences, Biochemistry, Genetics and Molecular Biology, Life Sciences, Metabolic Disorders and Biochemical Genetics, Clinical Biochemistry, Epigenetic Modifications and Their Functional Implications, Molecular Biology, Epigenetic Reprogramming, Biology, Phenotype, Zebrafish, Human genetics, Genetic heterogeneity, Allele, Allelic heterogeneity, Mendelian inheritance, Gene, CRISPR, Computational biology, Genotype

الوصف: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship.Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity.A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and ... : ارتبطت المتغيرات الثنائية في OGDHL، التي تشفر جزءًا من مركب نازعة الهيدروجين ألفا كيتوغلوتارات، باضطرابات عصبية ونمائية عصبية غير متجانسة للغاية. ومع ذلك، لا يزال يتعين تأكيد صحة هذه الرابطة. تم تعيين مجموعة ثانية من مرضى OGDHL لتقييم العلاقة بين الجينات والأمراض بعناية. باستخدام نهج النمط الجيني غير المتحيز أولاً، قمنا بفحص مجموعات بيانات تسلسل مجمعة كبيرة ومتعددة الأعراق في جميع أنحاء العالم لمتغيرات OGDHL ثنائية الأليل. استخدمنا CRISPR/Cas9 لتوليد الضربات القاضية لأسماك الزرد من ogdhl و ogdh paralogs و dhtkd1 للتحقيق في العلاقات الوظيفية والتأثير أثناء النمو. تم إجراء تكملة وظيفية مع نصوص متغيرة للمريض لتقييم وظائف البروتين بشكل منهجي كقراءة للأمراض. أظهرت مجموعة من 14 فردًا من 12 عائلة غير ذات صلة أنماطًا ظاهرية سريرية شديدة التباين، حيث قدم معظمهم متغيرًا إضافيًا واحدًا على الأقل، مما قد يمثل نمطًا ظاهريًا مختلطًا ويعقد الفهم الظاهري. كما كشفنا عن عدم تجانس سريري شديد وترددات أليل عالية، وأحيانًا لا تتوافق مع اضطراب متنحي نافذ تمامًا. تم اختبار cDNA البشري للمتغيرات الموصوفة سابقًا والجديدة في نموذج ...

العلاقة: https://dx.doi.org/10.60692/cazgw-bny33Test

الإتاحة: https://doi.org/10.60692/fxs8z-hsy7510.60692/cazgw-bny33Test

المؤلفون: Reem AlNeyadi, MD, Shaden Abdelhadi, MD, FRCP Edin, Zbigniew Ruszczak, MD, PhD, FECP Edin

المصدر: JAAD Case Reports, Vol 24, Iss , Pp 11-13 (2022)

مصطلحات موضوعية: acitretin, allelic heterogeneity, Chanarin-Dorfman syndrome, collodion membrane, ichthyosis, Dermatology, RL1-803

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2352512622001436Test; https://doaj.org/toc/2352-5126Test

الوصول الحر: https://doaj.org/article/72b021f2621546a696a791fc3b37b3b0Test

المؤلفون: Hormozdiari, Farhad, Zhu, Anthony, Kichaev, Gleb, Ju, Chelsea J-T, Segrè, Ayellet V, Joo, Jong Wha J, Won, Hyejung, Sankararaman, Sriram, Pasaniuc, Bogdan, Shifman, Sagiv, Eskin, Eleazar

المصدر: American journal of human genetics. 100(5)

مصطلحات موضوعية: Humans, Gene Frequency, Linkage Disequilibrium, Phenotype, Alleles, Quantitative Trait Loci, Models, Molecular, Databases, Genetic, Genetic Association Studies, allelic heterogeneity, causal variants, complex traits, eQTL, gene expression, Biotechnology, Prevention, Human Genome, Genetics, Biological Sciences, Medical and Health Sciences, Genetics & Heredity

الوصف: Recent successes in genome-wide association studies (GWASs) make it possible to address important questions about the genetic architecture of complex traits, such as allele frequency and effect size. One lesser-known aspect of complex traits is the extent of allelic heterogeneity (AH) arising from multiple causal variants at a locus. We developed a computational method to infer the probability of AH and applied it to three GWASs and four expression quantitative trait loci (eQTL) datasets. We identified a total of 4,152 loci with strong evidence of AH. The proportion of all loci with identified AH is 4%-23% in eQTLs, 35% in GWASs of high-density lipoprotein (HDL), and 23% in GWASs of schizophrenia. For eQTLs, we observed a strong correlation between sample size and the proportion of loci with AH (R2 = 0.85, p = 2.2 × 10-16), indicating that statistical power prevents identification of AH in other loci. Understanding the extent of AH may guide the development of new methods for fine mapping and association mapping of complex traits.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1xw2m0t3Test

المؤلفون: Matteo Botti, Vito Terlizzi, Michela Francalanci, Daniela Dolce, Maria Chiara Cavicchi, Anna Silvia Neri, Valeria Galici, Gianfranco Mergni, Lucia Zavataro, Claudia Centrone, Filippo Festini, Giovanni Taccetti

المصدر: Italian Journal of Pediatrics, Vol 47, Iss 1, Pp 1-8 (2021)

مصطلحات موضوعية: Cystic fibrosis, Newborn screening for cystic fibrosis CF NBS, CFTR allelic heterogeneity, Immunoreactive trypsinogen, DNA molecular analysis, Pediatrics, RJ1-570

الوصف: Abstract Background Cystic fibrosis (CF) is a life-threatening disease affecting about 1:3000 newborns in Caucasian populations. The introduction of newborn screening for cystic fibrosis (CF NBS) has improved the clinical outcomes of individuals with CF through early diagnosis and early treatment. NBS strategies have been implemented over time. CF NBS was introduced extensively in 1984 in Tuscany, a region with 3.7 million people, characterized by a high allelic heterogeneity of CFTR gene. Aim and methods The aim of the study is to present the results from 34 years (1984–2018) of CF NBS, retrospectively evaluating the sensitivity, specificity and predictive values of the tests. In particular, we studied the impact of the introduction of DNA molecular analysis in NBS in a region with high allelic heterogeneity, such as Tuscany. Results Over these 34 years, 919,520 neonates were screened, using four different NBS strategies. From 1984 to 1991, CF NBS was performed by the determination of albumin on dried meconium (sensitivity 68.75%; specificity 99.82%). Subsequently, the analysis of immunoreactive trypsinogen on a blood spot was adopted as CF NBS protocol (sensitivity 83.33%; specificity 99.77%). From 1992 to 2010, this strategy was associated with lactase meconium dosage: IRT1/IRT2 + LACT protocol (sensitivity 87.50%; specificity 99.82%). From 2011, when the existing algorithm was integrated by analysis of CF causing variants of the CFTR gene (IRT1/IRT2 + LACT + IRT1/DNA protocol), a substantial improvement in sensitivity was seen (senisitivity 96.15%; specificity 99.75%). Other improved parameters with DNA analysis in the NBS programme, compared with the previous method, were the diagnosis time (52 days vs. 38 days) and the recall rate (0.58 to 0.38%). Conclusion The inclusion of DNA analysis in the NBS was a fundamental step in improving sensitivity, even in a region with high allelic variability.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1824-7288Test

الوصول الحر: https://doaj.org/article/2cd82b90d17544b1ba359d6a11113bc5Test

المؤلفون: Anqi Zhu (1488514), Nana Matoba (5410757), Emma P. Wilson (10668453), Amanda L. Tapia (8174091), Yun Li (692280), Joseph G. Ibrahim (7241318), Jason L. Stein (4501942), Michael I. Love (5683529)

مصطلحات موضوعية: Medicine, Genetics, Plant Biology, Computational Biology, Biological Sciences not elsewhere classified, Mathematical Sciences not elsewhere classified, eQTL, loci, MRLocu, Bayesian estimation, allelic heterogeneity Expression, gene-to-trait mediation effect, method, two-sample Mendelian Randomization, gene expression, GWAS summary data, allelic heterogeneity, MR analysis step, non-coding genome-wide association .

الوصف: (PDF)

العلاقة: https://figshare.com/articles/journal_contribution/Description_of_statistical_methods_used_in_MRLocus_/14448915Test

الإتاحة: https://doi.org/10.1371/journal.pgen.1009455.s001Test

المؤلفون: Anqi Zhu (1488514), Nana Matoba (5410757), Emma P. Wilson (10668453), Amanda L. Tapia (8174091), Yun Li (692280), Joseph G. Ibrahim (7241318), Jason L. Stein (4501942), Michael I. Love (5683529)

مصطلحات موضوعية: Medicine, Genetics, Plant Biology, Computational Biology, Biological Sciences not elsewhere classified, Mathematical Sciences not elsewhere classified, eQTL, loci, MRLocu, Bayesian estimation, allelic heterogeneity Expression, gene-to-trait mediation effect, method, two-sample Mendelian Randomization, gene expression, GWAS summary data, allelic heterogeneity, MR analysis step, non-coding genome-wide association .

الوصف: (PDF)

العلاقة: https://figshare.com/articles/journal_contribution/Supplementary_Table_and_Figures_/14448918Test

الإتاحة: https://doi.org/10.1371/journal.pgen.1009455.s002Test