Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec

Physical activity and sedentary behavior following pediatric burns - a preliminary investigation using objective activity monitoring

Background: Adequate levels of regular physical activity (PA) are crucial for health and well-being. Pediatric burn injuries can have major physiological consequences in both the short and long term. The question is whether these consequences affect post burn PA levels. This study therefore aimed to describe PA and sedentary behavior (SB) in children and adolescents 1-5 years after burn injury. Methods: Daily PA and SB were monitored in 20 children and adolescents (12 boys and 8 girls, aged 6-17 years, with burns covering 10-37% of total body surface area, 1-5 years post burn) for 1 week using the ActiGraph GTX3+ accelerometer. Activity counts were categorized into SB, light PA, moderate PA, vigorous PA, moderate-to-vigorous PA (MVPA), and total PA. Outcomes were compared with non-burned reference values and PA levels recommended by the World Health Organization (WHO). Results: The participants spent about 5.1 h per day on total PA and 7.4 h on SB. Most of the active time (~ 83%) was categorized as light PA. Thirty-five percent of the group, especially the young boys, spent on average ≥ 60 min on MVPA per day. The boys, although with large interindividual differences, spent more time on MVPA than the girls (p < .005). Older age was associated with less PA time, while more time was spent sedentary. No trends were found indicating an effect of burn characteristics, time post burn, or length of hospital stay, and no differences were found with non-burned peers. Conclusion: Duration and intensity of PA and SB in children and adolescents 1-5 years after burn injury were similar to non-burned peers. However, only 35% of the group met the WHO physical activity recommendation. Given the increased long term risk for physical conditions following pediatric burns, physical activity should be encouraged in this vulnerable population. Trial registration: The study is registered in the National Academic Research and Collaborations Information System of the Netherlands (OND1348800)

Additional file 2: of Physical activity and sedentary behavior following pediatric burns – a preliminary investigation using objective activity monitoring

The systematic effect of epoch length. This figure shows the systematic overestimation of time spent in light physical activity and the systematic underestimation of both time in vigorous physical activity and sedentary behavior, when 60s–epochs are used rather than 15 s–epochs. Abbreviations: SB = sedentary behavior; PA = physical activity; min = minutes, sec = second. (TIFF 969 kb

Perceived fatigue following pediatric burns

Purpose: Fatigue is a common consequence of numerous pediatric health conditions. In adult burn survivors, fatigue was found to be a major problem. The current cross-sectional study is aimed at determining the levels of perceived fatigue in pediatric burn survivors. Methods: Perceived fatigue was assessed in 23 children and adolescents (15 boys and 8 girls, aged 6-18 years, with burns covering 10-46% of the total body surface area, 1-5 years post burn) using both child self- and parent proxy reports of the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale. Outcomes were compared with reference values of non burned peers. Results: At group level, pediatric burn survivors did not report significantly more symptoms of fatigue than their non-burned peers. Individual assessments showed, however, that four children experienced substantial symptoms of fatigue according to the child self-reports, compared to ten children according to the parent proxy reports. Furthermore, parents reported significantly more symptoms of fatigue than the children themselves. Age, gender, extent of burn, length of hospital stay, and number of surgeries could not predict the level of perceived fatigue post-burn. Conclusions: Our results suggest that fatigue is prevalent in at least part of the pediatric burn population after 1-5 years. However, the fact that parents reported significantly more symptoms of fatigue then the children themselves, hampers evident conclusions. It is essential for clinicians and therapists to consider both perspectives when evaluating pediatric fatigue after burn and to determine who needs special attention, the pediatric burn patient or its parent

Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation

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Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation

Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals. To identify additional genetic factors, hierarchical clustering of the plasma glycomics data was done, which indicated a subgroup of four patients that shared a unique glycomics signature of hybrid type N-glycans. In two siblings, compound heterozygous mutations were found in SLC10A7, a gene of unknown function in human. These included a missense mutation that disrupted transmembrane domain 4 and a mutation in a splice acceptor site resulting in skipping of exon 9. The two other individuals showed a complete loss of SLC10A7 mRNA. The patients' phenotype consisted of amelogenesis imperfecta, skeletal dysplasia, and decreased bone mineral density compatible with osteoporosis. The patients' phenotype was mirrored in SLC10A7 deficient zebrafish. Furthermore, alizarin red staining of calcium deposits in zebrafish morphants showed a strong reduction in bone mineralization. Cell biology studies in fibroblasts of affected individuals showed intracellular mislocalization of glycoproteins and a defect in post-Golgi transport of glycoproteins to the cell membrane. In contrast to yeast, human SLC10A7 localized to the Golgi. Our combined data indicate an important role for SLC10A7 in bone mineralization and transport of glycoproteins to the extracellular matrix