Gene-gene Interaction Analyses for Atrial Fibrillation

Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in a

Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.BH

Discovery of novel heart rate-associated loci using the Exome Chip

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies

Is occupation a good predictor of self-rated health in China?

China's rapidly changing economic landscape has led to widening social inequalities. Occupational status in terms of occupational type and prestige may reflect these socio-structural shifts of social position and be more predictive of self-rated health status than income and education, which may only reflect more gradual acquisitions of social status over time. The goals of this study were to understand the role of occupational status in predicting self-rated health, which is well known to be associated with long-term mortality, as well as compare the occupational status to the other major socioeconomic indicators of income and education.Data from the 2010 baseline surveys of the China Family Panel Studies, which utilized multi-stage probability sampling with implicit stratification was used. Logistic regression was used to examine the relationship of various socioeconomic indicators (i.e. occupational status, income, and education) with self-rated health as the primary outcome of interest. A series of models considered the associations of occupational category or occupational prestige with self-rated health.The final sample consisted of 14,367 employed adults aged 18-60, which was nationally representative of working adults in China. We found that occupation was not a major predictor of self-rated health in China when age, ethnicity, location, marital status, physical and mental health status were controlled for, with the exception of women working in lower grade management and professional jobs (OR = 1.82, 95% CI: 1.03-3.22). In comparison, income followed by education exhibited greater association with self-rated health. The highest income group had the least probability to report poor health (In men: OR = 0.30, 95% CI: 0.21-0.43. In women: OR = 0.44, 95% CI: 0.26-0.73). People educated with junior high school had better self-rated health than those with primary and below education level (In men: OR = 0.62, 95% CI: 0.50-0.75. In women: OR = 0.53, 95% CI: 0.42-0.68). Income, education and occupation were correlated with each other.Within the context of rapid societal changes in China, income and its implications for greater healthcare access and benefits had the greatest association with self-rated health followed by education. Occupational status was not associated. Occupational categories and prestige should be better adapted to reflect China's unique sociopolitical and historical context

ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest

Preparation, electronic structure and photoluminescence properties of RE (RE = Ce, Yb)-activated SrAlSi4N7 phosphors

The electronic structure of SrAlSi4N7 was calculated using the CASTEP code and SrAlSi4N7 is an intermediate band gap semiconductor with an indirect energy gap of 3.6 eV. Ce3+ and Yb2+-activated SrAlSi4N7 samples were prepared by a solid-state reaction method at high temperature, and their photoluminescence properties were investigated. SrAlSi4N7:Ce3+ shows a broad band emission in the wavelength range of 450–700 nm, originating from the 5d1–4f1 transition of Ce3+. The emission band of Ce3+ shifts to longer wavelength with an increase of Ce3+ concentration due to the increased Stokes shift and reabsorption by Ce3+. SrAlSi4N7:Yb2+ can be excited efficiently over a broad spectral range between 300 and 550 nm, and exhibits a single intense red emission at 600 nm with a full width at half maximum of 95 nm due to the electronic transitions from the excited state of 4f135d to the ground state 4f14 of Yb2+. The low energy of Yb2+ emission in SrAlSi4N7 can be attributed to the large nephelauxetic effect and crystal field splitting due to the coordination of Yb2+ by nitrogen. In addition, Sr1-2xCexLixAlSi4N7 shows higher thermal stability in air than that of Sr1-yYbyAlSi4N7 (0 = x, y = 0.1). A white-light LED can be generated by using single SrAlSi4N7:Ce3+ as the wavelength conversion phosphor combined with a blue LED chip (InGaN). The obtained LED exhibits a luminous efficiency of 74.3 lm W-1 at a corrected color temperature (CCT) up to 6350 K, and the color rendering index (CRI Ra) is around 78. These novel developed yellow-red phosphors have potential applications in spectral conversion materials for white-LEDs