Human Heredity最新文献

{"title":"Title Page/Table of Contents","authors":"J. Wang","doi":"10.1159/000495548","DOIUrl":"https://doi.org/10.1159/000495548","url":null,"abstract":"","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"83 1","pages":"101 - 104"},"PeriodicalIF":1.8,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000495548","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46881049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Bayesian Hierarchical Framework for Pathway Analysis in Genome-Wide Association Studies.","authors":"Lei Zhang,&nbsp;Charalampos Papachristou,&nbsp;Pankaj K Choudhary,&nbsp;Swati Biswas","doi":"10.1159/000508664","DOIUrl":"https://doi.org/10.1159/000508664","url":null,"abstract":"<p><strong>Background: </strong>Pathway analysis allows joint consideration of multiple SNPs belonging to multiple genes, which in turn belong to a biologically defined pathway. This type of analysis is usually more powerful than single-SNP analyses for detecting joint effects of variants in a pathway.</p><p><strong>Methods: </strong>We develop a Bayesian hierarchical model by fully modeling the 3-level hierarchy, namely, SNP-gene-pathway that is naturally inherent in the structure of the pathways, unlike the currently used ad hoc ways of combining such information. We model the effects at each level conditional on the effects of the levels preceding them within the generalized linear model framework. To deal with the high dimensionality, we regularize the regression coefficients through an appropriate choice of priors. The model is fit using a combination of iteratively weighted least squares and expectation-maximization algorithms to estimate the posterior modes and their standard errors. A normal approximation is used for inference.</p><p><strong>Results: </strong>We conduct simulations to study the proposed method and find that our method has higher power than some standard approaches in several settings for identifying pathways with multiple modest-sized variants. We illustrate the method by analyzing data from two genome-wide association studies on breast and renal cancers.</p><p><strong>Conclusion: </strong>Our method can be helpful in detecting pathway association.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 6","pages":"240-255"},"PeriodicalIF":1.8,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000508664","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38414153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of miR-210 in the Biological System: A Current Overview.","authors":"Xu Hui,&nbsp;Hisham Al-Ward,&nbsp;Fahmi Shaher,&nbsp;Chun-Yang Liu,&nbsp;Ning Liu","doi":"10.1159/000509280","DOIUrl":"https://doi.org/10.1159/000509280","url":null,"abstract":"<p><strong>Background: </strong>MicroRNAs (miRNAs) represent a group of non-coding RNAs measuring 19-23 nucleotides in length and are recognized as powerful molecules that regulate gene expression in eukaryotic cells. miRNAs stimulate the post-transcriptional regulation of gene expression via direct or indirect mechanisms.</p><p><strong>Summary: </strong>miR-210 is highly upregulated in cells under hypoxia, thereby revealing its significance to cell endurance. Induction of this mRNA expression is an important feature of the cellular low-oxygen response and the most consistent and vigorous target of HIF. Key Message: miR-210 is involved in many cellular functions under the effect of HIF-1α, including the cell cycle, DNA repair, immunity and inflammation, angiogenesis, metabolism, and macrophage regulation. It also plays an important regulatory role in T-cell differentiation and stimulation.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 6","pages":"233-239"},"PeriodicalIF":1.8,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000509280","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38458660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 Plot: Decomposition and Graphical Display of the RV Coefficient, with Application to Genetic and Brain Imaging Biomarkers of Alzheimer's Disease.","authors":"JinCheol Choi, Donghuan Lu, Mirza Faisal Beg, Jinko Graham, Brad McNeney","doi":"10.1159/000501334","DOIUrl":"10.1159/000501334","url":null,"abstract":"<p><strong>Background/aims: </strong>Alzheimer's disease (AD) is a chronic neurodegenerative disease that causes memory loss and a decline in cognitive abilities. AD is the sixth leading cause of death in the USA, affecting an estimated 5 million Americans. To assess the association between multiple genetic variants and multiple measurements of structural changes in the brain, a recent study of AD used a multivariate measure of linear dependence, the RV coefficient. The authors decomposed the RV coefficient into contributions from individual variants and displayed these contributions graphically.</p><p><strong>Methods: </strong>We investigate the properties of such a \"contribution plot\" in terms of an underlying linear model, and discuss shrinkage estimation of the components of the plot when the correlation signal may be sparse.</p><p><strong>Results: </strong>The contribution plot is applied to simulated data and to genomic and brain imaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).</p><p><strong>Conclusions: </strong>The contribution plot with shrinkage estimation can reveal truly associated explanatory variables.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 1","pages":"59-72"},"PeriodicalIF":1.1,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9008771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48183543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estimating Uterine Fibroid SNP-Based Heritability in European American Women with Imaging-Confirmed Fibroids.","authors":"Michael J Bray,&nbsp;Lea K Davis,&nbsp;Eric S Torstenson,&nbsp;Sarah H Jones,&nbsp;Todd L Edwards,&nbsp;Digna R Velez Edwards","doi":"10.1159/000501335","DOIUrl":"https://doi.org/10.1159/000501335","url":null,"abstract":"<p><strong>Background: </strong>Heritability estimates (including twin and single nucleotide polymorphism [SNP]-based heritability studies) for fibroids have been inconsistent across prior studies ranging between 9 and 69%. These inconsistencies are due to variations in study design and included populations. A major design issue has been lack of imaging confirmation to identify controls, where asymptomatic women without imaging confirmation may be misclassified as controls leading to an attenuation of heritability estimates. To reconcile the differences in prior heritability estimates and the impact of misclassification of controls on heritability, we determined SNP-based heritability and characterized the genetic architecture of pelvic image-confirmed fibroid cases and controls.</p><p><strong>Methods: </strong>Analyses were performed among women of European American descent using genome-wide SNP data from BioVU, a clinical database composed of DNA linked to de-identified electronic health records. We estimated the genetic variance explained by all SNPs using Genome-Wide Complex Trait Analysis on imputed data. Fibroid cases and controls were identified using a previously reported phenotyping algorithm that required pelvic imaging confirmation.</p><p><strong>Results: </strong>In total, we used 1,067 image-confirmed fibroid cases and 1,042 image-confirmed fibroid controls. The SNP-based heritability estimate for fibroid risk was h2 = 0.33 ± 0.18 (p = 0.040). We investigated the relationship between heritability per chromosome and chromosome length (r2 < 1%), with chromosome 8 explaining the highest proportion of variance for fibroid risk. There was no enrichment for intergenic or genic SNPs for the fibroid SNP-based heritability. Excluding loci previously associated with fibroid risk from genome-wide association study did not attenuate fibroid heritability suggesting that loci associating with fibroid risk are yet to be discovered.</p><p><strong>Conclusions: </strong>We observed that fibroid SNP-based heritability was higher than the previous estimate using genome-wide SNP data that relied on self-reported outcomes, but within the range of prior twin pair studies. Furthermore, these data support that imprecise phenotyping can significantly affect the ability to estimate heritability using genotype data.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 2","pages":"73-81"},"PeriodicalIF":1.8,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000501335","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9824469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel IDS Variants Identified in Three Unrelated Pakistani Patients Affected with Mucopolysaccharidosis Type II (Hunter Syndrome).","authors":"Bibi Zubaida,&nbsp;Hajira Batool,&nbsp;Huma Arshad Cheema,&nbsp;Nadia Waheed,&nbsp;Muhammad Naeem","doi":"10.1159/000510065","DOIUrl":"https://doi.org/10.1159/000510065","url":null,"abstract":"<p><strong>Introduction: </strong>Mucopolysaccharidosis type II (MPS-II) or Hunter syndrome is a rare X-linked recessive disorder caused by genetic lesions in the IDS gene, encoding the iduronate-2-sulfatase (IDS) enzyme, disrupting the metabolism of certain sulfate components of the extracellular matrix. Thus, the undegraded components, also known as glycosaminoglycans, accumulate in multiple tissues resulting in multisystemic abnormalities.</p><p><strong>Objective: </strong>To uncover causative genetic lesions in probands of three unrelated Pakistani families affected with rare X-linked recessive Hunter syndrome.</p><p><strong>Methods: </strong>Screening of the IDS gene was performed in six individuals (three patients and their mothers) through whole genomic DNA extraction from peripheral blood followed by PCR and Sanger sequencing. MutationTaster, PROVEAN, Human Splicing Finder, Swiss-Model, and SwissPdbViewer were used for in silico analysis of identified variants.</p><p><strong>Results: </strong>All probands were presented with coarse facies, recurrent respiratory tract infection, and reduced IDS activity. Molecular screening of IDS identified three different pathogenic variants including a novel duplication variant c.114_117dupCGTT, a novel splice site variant c.1006 + 1G>C, and a nonsense variant c.1165C>T. In silico analysis unanimously revealed the pathogenic nature of the variants due to their deleterious effects upon the encoded enzyme.</p><p><strong>Conclusion: </strong>Identified variants predictably lead to either the expression of a nonfunctional enzyme due to partial loss of SD1 and complete loss of SD2 subdomains or a complete lack of the IDS enzyme as a result of nonsense-mediated mRNA decay. Our study provides the first genetic depiction of MPS-II in Pakistan, expands the global IDS mutation spectrum, may provide insights into the three-dimensional structure of IDS, and should benefit the affected families in genetic counseling and prenatal diagnosis.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 6","pages":"279-286"},"PeriodicalIF":1.8,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000510065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38510392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heritability and Sex-Specific Genetic Effects of Self-Reported Physical Activity in a Brazilian Highly Admixed Population.","authors":"Jean Michel Rocha Sampaio Leite, Júlia Maria Pavan Soler, Andréa Roseli Vançan Russo Horimoto, Rafael O Alvim, Alexandre C Pereira","doi":"10.1159/000506007","DOIUrl":"10.1159/000506007","url":null,"abstract":"<p><strong>Introduction: </strong>The engagement in sports or habitual physical activity (PA) has shown an extensive protective role against multiple diseases such as cancer, obesity, and many others. Additionally, PA has also a significant impact on life quality, since it aids with managing stress, preserving cognitive function and memory, and preventing fractures in the elderly.</p><p><strong>Objective: </strong>Considering there has been multiple evidence showing that genetic variation underpins variation of PA-related traits, we aimed to estimate the heritability (h2) of these phenotypes in a sample from the Brazilian population and assess whether males and females differ in relation to those estimates.</p><p><strong>Methods: </strong>2,027 participants from a highly admixed population from Baependi, MG, Brazil, had information regarding their PA and sedentary behavior (SB) phenotypes collected through a questionnaire (IPAQ-SF). After data cleaning and transformation procedures, we obtained four variables to be evaluated: total PA (TPA MET), walking time, (WK MET), moderate-vigorous PA (MVPA MET), and SB. A model selection procedure was performed using a single-step covariate inclusion approach. We tested for BMI, waist, hip and neck circumferences, smoking, and depression separately, and performed correlation tests among covariates. Linear mixed models, selection procedure, and the variance components approach to estimate h2 were implemented using SOLAR-Eclipse 8.3.1.</p><p><strong>Results: </strong>We obtained estimates of 0.221, 0.109, 0.226, and 0 for TPA MET, WK MET, MVPA MET, and SB, respectively. We found evidence for gene-sex interactions, with males having higher sex-specific heritabilities than females for TPA MET and MVPA MET. In addition, we found higher estimates of the genetic variance component in males than females for most phenotypes.</p><p><strong>Discussion/conclusion: </strong>The heritability estimates presented in this work show a moderate heritable set of genetic factors affecting PA in a sample from the Brazilian population. The evaluation of the genetic variance component suggests segregating genetic factors in male individuals are more heterogeneous, which can explain why men globally tend to need to practice more intense PA than women to achieve similar health benefits. Hence, these findings have significant implications for the understanding of the genetic architecture of PA and might aid to promote health in the future.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 3","pages":"151-158"},"PeriodicalIF":1.1,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212208/pdf/nihms-1585090.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37669587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mathematical Properties of Linkage Disequilibrium Statistics Defined by Normalization of the Coefficient D = pAB - pApB.","authors":"Jonathan T L Kang,&nbsp;Noah A Rosenberg","doi":"10.1159/000504171","DOIUrl":"https://doi.org/10.1159/000504171","url":null,"abstract":"<p><strong>Background: </strong>Many statistics for measuring linkage disequilibrium (LD) take the form of a normalization of the LD coefficient D. Different normalizations produce statistics with different ranges, interpretations, and arguments favoring their use.</p><p><strong>Methods: </strong>Here, to compare the mathematical properties of these normalizations, we consider 5 of these normalized statistics, describing their upper bounds, the mean values of their maxima over the set of possible allele frequency pairs, and the size of the allele frequency regions accessible given specified values of the statistics.</p><p><strong>Results: </strong>We produce detailed characterizations of these properties for the statistics d and ρ, analogous to computations previously performed for r2. We examine the relationships among the statistics, uncovering conditions under which some of them have close connections.</p><p><strong>Conclusion: </strong>The results contribute insight into LD measurement, particularly the understanding of differences in the features of different LD measures when computed on the same data.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 3","pages":"127-143"},"PeriodicalIF":1.8,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000504171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37633432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Homozygous RAG1 Gene Mutation in a Case of Combined Immunodeficiency: Clinical, Molecular, and Computational Analysis.","authors":"Soukaina Essadssi,&nbsp;Ibtihal Benhsaien,&nbsp;Amina Bakhchane,&nbsp;Hicham Charoute,&nbsp;Houria Abdelghaffar,&nbsp;Ahmed Aziz Bousfiha,&nbsp;Abdelhamid Barakat","doi":"10.1159/000510062","DOIUrl":"https://doi.org/10.1159/000510062","url":null,"abstract":"<p><strong>Background: </strong>The recombination-activating gene 1 and 2 (RAG1/RAG2) proteins are essential to initiate the V(D)J recombination process, the result is a diverse repertoire of antigen receptor genes and the establishment of the adaptive immunity. RAG1 mutations can lead to multiple forms of combined immunodeficiency.</p><p><strong>Methods: </strong>In this report, whole exome sequencing was performed in a Moroccan child suffering from combined immunodeficiency, with T and B lymphopenia, autoimmune hemolytic anemia, and cytomegalovirus (CMV) infection.</p><p><strong>Results: </strong>After filtering data and Sanger sequencing validation, one homozygous mutation c.2446G>A (p.Gly816Arg) was identified in the RAG1 gene.</p><p><strong>Conclusion: </strong>This finding expands the spectrum of immunological and genetic profiles linked to RAG1 mutation, it also illustrates the necessity to consider RAG1 immunodeficiency in the presence of autoimmune hemolytic anemia and CMV infection, even assuming the immunological phenotype appears more or less normal.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 6","pages":"272-278"},"PeriodicalIF":1.8,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000510062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38600712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Power and Sample Size Calculations for Genetic Association Studies in the Presence of Genetic Model Misspecification.","authors":"Camille M Moore,&nbsp;Sean A Jacobson,&nbsp;Tasha E Fingerlin","doi":"10.1159/000508558","DOIUrl":"https://doi.org/10.1159/000508558","url":null,"abstract":"<p><strong>Introduction: </strong>When analyzing data from large-scale genetic association studies, such as targeted or genome-wide resequencing studies, it is common to assume a single genetic model, such as dominant or additive, for all tests of association between a given genetic variant and the phenotype. However, for many variants, the chosen model will result in poor model fit and may lack statistical power due to model misspecification.</p><p><strong>Objective: </strong>We develop power and sample size calculations for tests of gene and gene × environment interaction, allowing for misspecification of the true mode of genetic susceptibility.</p><p><strong>Methods: </strong>The power calculations are based on a likelihood ratio test framework and are implemented in an open-source R package (\"genpwr\").</p><p><strong>Results: </strong>We use these methods to develop an analysis plan for a resequencing study in idiopathic pulmonary fibrosis and show that using a 2-degree of freedom test can increase power to detect recessive genetic effects while maintaining power to detect dominant and additive effects.</p><p><strong>Conclusions: </strong>Understanding the impact of model misspecification can aid in study design and developing analysis plans that maximize power to detect a range of true underlying genetic effects. In particular, these calculations help identify when a multiple degree of freedom test or other robust test of association may be advantageous.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 6","pages":"256-271"},"PeriodicalIF":1.8,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000508558","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38201303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}