Genome-wide association and Mendelian randomization analysis provide insights into the shared genetic architecture between high-dimensional electrocardiographic features and ischemic heart disease
AbstractObservational studies have revealed that ischemic heart disease (IHD) has a unique manifestation on electrocardiographic (ECG). However, the genetic relationships between IHD and ECG remain unclear. We took 12-lead ECG as phenotypes to conduct genome-wide association studies (GWAS) for 41,960 samples from UK-Biobank (UKB). By leveraging large-scale GWAS summary of ECG and IHD (downloaded from FinnGen database), we performed LD score regression (LDSC), Mendelian randomization (MR), and polygenic risk score (PRS) regression to explore genetic relationships between IHD and ECG. Finally, we constructed an XGBoost model...
Source: Human Genetics - January 5, 2024 Category: Genetics & Stem Cells Source Type: research
Predicting the impact of rare variants on RNA splicing in CAGI6
AbstractVariants which disrupt splicing are a frequent cause of rare disease that have been under-ascertained clinically. Accurate and efficient methods to predict a variant ’s impact on splicing are needed to interpret the growing number of variants of unknown significance (VUS) identified by exome and genome sequencing. Here, we present the results of the CAGI6 Splicing VUS challenge, which invited predictions of the splicing impact of 56 variants ascertained clinic ally and functionally validated to determine splicing impact. The performance of 12 prediction methods, along with SpliceAI and CADD, was compared on the 5...
Source: Human Genetics - January 3, 2024 Category: Genetics & Stem Cells Source Type: research
Mining local exome and HLA data to characterize pharmacogenetic variants in Saudi Arabia
AbstractPharmacogenomics (PGx) is a promising field of precision medicine where efficacy of drugs is maximized while side effects are minimized for individual patients. Knowledge of the frequency of PGx-relevant variants (pharmacovariants) in the local population is a pre-requisite to informed policy making. Unfortunately, such knowledge is largely lacking from the Middle East. Here, we describe the use of a large clinical exome database (n = 13,473) and HLA haplotypes (n = 64,737) from Saudi Arabia, one of the largest countries in the Middle East, along with previously published data from the local population to ...
Source: Human Genetics - December 30, 2023 Category: Genetics & Stem Cells Source Type: research
Recombination map tailored to Native Hawaiians may improve robustness of genomic scans for positive selection
AbstractRecombination events establish the patterns of haplotypic structure in a population and estimates of recombination rates are used in several downstream population and statistical genetic analyses. Using suboptimal maps from distantly related populations may reduce the efficacy of genomic analyses, particularly for underrepresented populations such as the Native Hawaiians. To overcome this challenge, we constructed recombination maps using genome-wide array data from two study samples of Native Hawaiians: one reflecting the current admixed state of Native Hawaiians (NH map) and one based on individuals of enriched P...
Source: Human Genetics - December 29, 2023 Category: Genetics & Stem Cells Source Type: research
Impact of calmodulin missense variants associated with congenital arrhythmia on the thermal stability and the degree of unfolding
We report an empirical method that estimates melting temperatures (Tm) from multi-transition thermal denaturation profiles of 16 variants of calmodulin (CaM) associated with congenital arrhythmia. Differences inTm estimated by empirical fitting correlate (for apo CaM variants) with those obtained by thermodynamic models. Most CaM variants were more stable than the wild type (WT) in the absence of Ca2+, but less stable in the presence of Ca2+, and displayed either WT-like or higher unfolding percentages in their apo-form, as evaluated by circular dichroism spectroscopy. (Source: Human Genetics)
Source: Human Genetics - December 28, 2023 Category: Genetics & Stem Cells Source Type: research
Regulation potential of transcribed simple repeated sequences in developing neurons
AbstractSimple repeated sequences (SRSs), defined as tandem iterations of microsatellite- to satellite-sized DNA units, occupy a substantial part of the human genome. Some of these elements are known to be transcribed in the context of repeat expansion disorders. Mounting evidence suggests that the transcription of SRSs may also contribute to normal cellular functions. Here, we used genome-wide bioinformatics approaches to systematically examine SRS transcriptional activity in cells undergoing neuronal differentiation. We identified thousands of long noncoding RNAs containing>200-nucleotide-long SRSs (SRS-lncRNAs), with...
Source: Human Genetics - December 28, 2023 Category: Genetics & Stem Cells Source Type: research
Impact of calmodulin missense variants associated with congenital arrhythmia on the thermal stability and the degree of unfolding
We report an empirical method that estimates melting temperatures (Tm) from multi-transition thermal denaturation profiles of 16 variants of calmodulin (CaM) associated with congenital arrhythmia. Differences inTm estimated by empirical fitting correlate (for apo CaM variants) with those obtained by thermodynamic models. Most CaM variants were more stable than the wild type (WT) in the absence of Ca2+, but less stable in the presence of Ca2+, and displayed either WT-like or higher unfolding percentages in their apo-form, as evaluated by circular dichroism spectroscopy. (Source: Human Genetics)
Source: Human Genetics - December 28, 2023 Category: Genetics & Stem Cells Source Type: research
Regulation potential of transcribed simple repeated sequences in developing neurons
AbstractSimple repeated sequences (SRSs), defined as tandem iterations of microsatellite- to satellite-sized DNA units, occupy a substantial part of the human genome. Some of these elements are known to be transcribed in the context of repeat expansion disorders. Mounting evidence suggests that the transcription of SRSs may also contribute to normal cellular functions. Here, we used genome-wide bioinformatics approaches to systematically examine SRS transcriptional activity in cells undergoing neuronal differentiation. We identified thousands of long noncoding RNAs containing>200-nucleotide-long SRSs (SRS-lncRNAs), with...
Source: Human Genetics - December 28, 2023 Category: Genetics & Stem Cells Source Type: research
Protein-centric omics integration analysis identifies candidate plasma proteins for multiple autoimmune diseases
AbstractIt remains challenging to translate the findings from genome-wide association studies (GWAS) of autoimmune diseases (AIDs) into interventional targets, presumably due to the lack of knowledge on how the GWAS risk variants contribute to AIDs. In addition, current immunomodulatory drugs for AIDs are broad in action rather than disease-specific. We performed a comprehensive protein-centric omics integration analysis to identify AIDs-associated plasma proteins through integrating protein quantitative trait loci datasets of plasma protein (1348 proteins and 7213 individuals) and totally ten large-scale GWAS summary stat...
Source: Human Genetics - December 24, 2023 Category: Genetics & Stem Cells Source Type: research
Delineation of the adult phenotype of Coffin –Siris syndrome in 35 individuals
AbstractCoffin –Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularl y on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants inARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collecte...
Source: Human Genetics - December 20, 2023 Category: Genetics & Stem Cells Source Type: research
