Human Heredity最新文献

Background: 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.

Methods: 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.

Results: 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.

Conclusion: Our method can be helpful in detecting pathway association.

Background: 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.

Summary: 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.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Introduction: 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.

Objective: To uncover causative genetic lesions in probands of three unrelated Pakistani families affected with rare X-linked recessive Hunter syndrome.

Methods: 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.

Results: 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.

Conclusion: 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.

Introduction: 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.

Objective: 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.

Methods: 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.

Results: 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.

Discussion/conclusion: 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.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.