Atrial Fibrillation: Pathogenesis, Predisposing Factors, and Genetics

Atrial fibrillation (AF) is the most frequent arrhythmia managed in clinical practice, and it is linked to an increased risk of death, stroke, and peripheral embolism. The Global Burden of Disease shows that the estimated prevalence of AF is up to 33.5 million patients. So far, successful therapeutic techniques have been implemented, with a high health-care cost burden. As a result, identifying modifiable risk factors for AF and suitable preventive measures may play a significant role in enhancing community health and lowering health-care system expenditures. Several mechanisms, including electrical and structural remodeling of atrial tissue, have been proposed to contribute to the development of AF. This review article discusses the predisposing factors in AF including the different pathogenic mechanisms, sedentary lifestyle, and dietary habits, as well as the potential genetic burden.

Updating preventive measures of children disability

The article provides an overview of special literature, which gives an opportunity to redefine some issues of disability prevention in children with rare (orphan) diseases, which will improve the organizational measures in this area. The prevention of children’s disability is considered as a system of measures to protect the health of the mother and child throughout childhood. The early disability prevention system in children and support for families raising children with disabilities remain among the main priorities of the State social policy of the Russian Federation. The authors describe modern technologies for reducing the genetic burden in the population from the point of view of preventing hereditary and congenital pathologies. They identify the priority areas of disability prevention in children with rare (orphan) diseases, i.e. introduction of prenatal and preimplantation diagnostics; use of the Prenatal Consultation organizational model; conducting a wider screening for congenital and hereditary metabolic diseases with the inclusion of the most common nosological forms of rare (orphan) diseases; finding pathogenetic therapy methods; increasing the knowledge of pediatricians about rare (orphan) diseases.

Whole Genome Sequencing Illuminates the Developmental Signatures of Human Language Ability

Language is the foundation of human social interaction, education, commerce, and mental health. The heritability underlying language is well-established, but our understanding of its genetic basis - and how it compares to that of more general cognitive functioning - remains unclear. To illuminate the language-specific contributions of rare and common variation, we performed whole genome sequencing in N=350 individuals, who were characterized with seven latent language phenotypes. We conducted region, gene, and gene set-based analyses to identify patterns of genetic burden that disproportionately explained these language factors compared to nonverbal IQ. These analyses identified language-specific associations with NDST4 and GRIN2A, with common variant replication of NDST4 in an independent sample. Rare variant burden analyses revealed three distinct functional profiles of genes that make contributions to language: a prenatally-expressed profile with enrichment for chromatin modifiers and broad neuropsychiatric risk, a postnatal cortex-expressed profile with enrichment for ion channels and cognitive/neuropsychiatric associations, and a postnatal, subcortically-expressed profile with enrichment of cilium-related proteins. Compared to a profile strongly associated with nonverbal IQ, these language-related profiles showed less intolerance to damaging variation, suggesting that the selection patterns acting on language differ from patterns linked to intellectual disability. Furthermore, we found evidence that rare potential reversions to an ancestral state are associated with poorer overall specific language ability. The breadth of these variant, gene, and profile associations suggest that while human-specific selection patterns do contribute to language, these are distributed broadly across numerous key mechanisms and developmental periods, and not in one or a few "language genes".

Missense variant in interleukin-6 signal transducer identified as susceptibility locus for rheumatoid arthritis in Chinese patients

Objectives: This study aims to uncover variants of large effect size and allele frequency below 5% by sequencing all extant genes associated with rheumatoid arthritis (RA) in a homogeneous patient cohort. Patients and methods: This retrospective study was conducted between January 2001 and December 2017. We selected Chinese RA patients positive for anti-citrullinated peptide antibody (ACPA). All the 128 known candidate genes identified through genome-wide association studies were sequenced in 48 RA patients (15 males, 33 females; mean age 53.32±8.98 years; range, 32 to 75 years) and 45 controls (11 males, 34 females; mean age 32.18±9.54; range, 21 to 57 years). The exonic regions of these genes were sequenced. The resultant data were analyzed for association using single variant association and pathway-based association enrichment tests. The genetic burden due to low-frequency variants was assessed with the C-alpha test. The candidate variants that showed significant association were validated in a larger cohort of 500 RA cases (71 males, 429 females; mean age 48.6±12.2 years; range, 24 to 92 years) and 500 controls (66 males, 434 females; mean age 32.3±10.1 years; range, 21 to 73 years). Results: Thirty-nine variants in 21 genes were identified using single variant association analysis and C-alpha test, with stepwise filtering. Among these, the missense variant in interleukin-6 signal transducer (IL-6ST) 5:55260065 (p.Cys47Phe) was significantly associated with RA in Chinese patients in Singapore. Conclusion: Our results suggest that a mutation in IL-6ST (5:55260065) confers risk of RA in Chinese patients in Singapore.

Indexes of Natural Selection, Migration and Reproductive Characteristics in Lutsk Population, West Ukraine

In human populations natural selection is shifting to the side of prenatal development and appears as negative outcomes of pregnancies such as spontaneous abortions, ectopic pregnancies and stillbirths. Therefore, it is important to study dynamics of changes in reproductive characteristics and selection indexes of the populations in order to predict possible problems and numbers of genetic burden in the populations. Ukraine is poorly studied in this area. The aim of the study was to investigate indicators which characterize the population structure of Lutsk city, the intensity of natural selection, migration and their dynamics in two generations. 583 post-reproductive age females were anonymously questioned. Age, places of birth of the couple, the number of pregnancies and their outcomes were considered. Results show that natural selection indexes (Crow’s indexes) are decreasing from the first generation (0,26) to the second (0,20). Migration coefficients in the population of Lutsk decreased from 0.89 to 0.82 per generation and show intensive urbanization of the city for the studied time. The efficiency of the migration is low, since the biggest number of migrants come from the villages of the Volyn region (45% for first generations and 64% for the second one), or adjacent regions of Ukraine (35% and 27%, respectively). The population of Lutsk has a narrowed type of reproduction, where average number of offspring per female equal 1,86 for the first generation and 1,73 for the second generation.

A Multi-Study Model-Based Evaluation of the Sequence of Imaging and Clinical Biomarker Changes in Huntington’s Disease

Understanding the order and progression of change in biomarkers of neurodegeneration is essential to detect the effects of pharmacological interventions on these biomarkers. In Huntington’s disease (HD), motor, cognitive and MRI biomarkers are currently used in clinical trials of drug efficacy. Here for the first time we use directly compare data from three large observational studies of HD (total N = 532) using a probabilistic event-based model (EBM) to characterise the order in which motor, cognitive and MRI biomarkers become abnormal. We also investigate the impact of the genetic cause of HD, cytosine-adenine-guanine (CAG) repeat length, on progression through these stages. We find that EBM uncovers a broadly consistent order of events across all three studies; that EBM stage reflects clinical stage; and that EBM stage is related to age and genetic burden. Our findings indicate that measures of subcortical and white matter volume become abnormal prior to clinical and cognitive biomarkers. Importantly, CAG repeat length has a large impact on the timing of onset of each stage and progression through the stages, with a longer repeat length resulting in earlier onset and faster progression. Our results can be used to help design clinical trials of treatments for Huntington’s disease, influencing the choice of biomarkers and the recruitment of participants.

HEREDITARY LOAD IN MEAT AND EGG CHICKENS OF VARIOUS ORIGIN

The aim of the study was to determine the spectrum and frequency of hereditary genetic defects of embryo development in meat and egg hens of different genetic origin, obtained during an experiment to study the effectiveness of crossing roosters of imported meat crosses with meat and egg females of domestic selection. All embryos that died during egg incubation were carefully examined to detect morphopathology. The main research method is pathomorphological analysis of genetic defects of dead embryos. The spectrum and frequency of morphological and anatomical hereditary defects of embryos were established during pathological and anatomical examination of incubation waste. During the autopsy of dead embryos, morphological disorders in the structure of the skeleton were determined, as well as various disproportions of its individual parts. In the meat-egg hens of the original maternal form during three years of monitoring with the highest frequency (2.11–6.06%) revealed such a defect in embryo development as "donald duck". This indicates that the bird is "contaminated" with a "harmful gene" that causes this abnormality. It is worth noting that in groups of chickens that were artificially inseminated with the semen of roosters of meat crosses, this hereditary defect was also recorded. In the descendants of the first and second generations, this anomaly was absent, possibly due to its transition to a heterozygous state. Thus, we can conclude that the allele that expresses this lethal has in its genotype a bird of the local subpopulation "K". Only in meat and egg hens of domestic selection a wide variety of double anomalies was found – four species with a frequency of 1.05–1.12%. Most likely, double abnormalities are the result of homozygosity of dead embryos simultaneously for two lethal genes. Whereas, in chickens of other studied groups, only single anomalies of dead embryos were found, among them "exencephaly", "crossed beak", "shortened beak". Genetic defect of embryos "exencephaly" was found in chickens of most groups. It is obvious that the gene that determines the manifestation of this anomaly is significantly distributed in meat and egg hens of domestic selection and roosters used crosses. And in chickens of the created synthetic population "K-5" only this hereditary defect is revealed. In meat and egg hens of subpopulation "K" (F10) of the original maternal form and in the group of females, which were inseminated with polysperm of meat cocks of the cross "Cobb-500", with a low frequency (0.78–1.12%) a single "crossed beak" anomaly was found among the frozen embryos. This anomaly was not detected in the offspring of the first generation and in groups of chickens inseminated with semen of overripe brood stock. And only in the "cobb" bird of the "K-51" group among the hereditary defects of the dead embryos was this anomaly identified. In meat-egg hens of F10 subpopulation "K" with a low frequency (1.12%) was found a hereditary defect of embryos "shortened beak". Then this anomaly was found only in the "cobb" bird of both the first and second generation. The data show that the hereditary factor that determines this defect, the descendants inherited from the cocks of the cross "Cobb-500". The level of genetic burden in meat and egg hens of the local subpopulation "K", depending on the generation, ranged from 5.26 to 8.99% and was wavy in nature. In the descendants of the first generation it is low – 1.64–4.17%, in the "ross" crossbreeds is much smaller compared to the "cobb". The descendants of the second generation of different origins also had a low hereditary burden – in the range of 4.35–5.88%, which does not exceed the maximum allowable species value of 8.0%. The results of the research showed that crossing meat-egg hens of domestic selection with roosters of imported meat crosses "Cobb-500" and "Ross-308" did not lead to significant "contamination" of genotypes of F1-F2 offspring with lethal genes. This indicates a low share in the heredity of the used offspring of hidden carriers of "defective" genes. This may be due to the high selection of birds of foreign crosses, which does not contribute to the accumulation in its gene pool of lethal genes that cause embryonic developmental abnormalities. In chickens of the created synthetic population "K-5" the level of genetic burden is low (3.03%), which indicates the relative "purity" of this bird from lethal genes.

Flux vs burden: biosensor optimization for dynamic pathway engineering

Recent progress in synthetic biology allows the construction of dynamic control circuits for metabolic engineering. This technology promises to overcome many challenges encountered in traditional pathway engineering, thanks to their ability to self-regulate gene expression in response to bioreactor perturbations. The central components in these control circuits are metabolite biosensors that read out pathway signals and actuate enzyme expression. However, the construction of metabolite biosensors is laborious and currently a major bottleneck for strain design. Here we present a general method for biosensor design based on multiobjective optimization. Our approach produces libraries of biosensors that optimally trade-off production flux against the genetic burden on the host. We explore properties of control architectures built in the literature, and identify their advantages and caveats in terms of performance and robustness to growth conditions or leaky promoters. We demonstrate the optimality of a control circuit for glucaric acid production in Escherichia coli, which has been shown to increase titer by 2.5-fold as compared to static designs. Our results lay the groundwork for the automated design of control circuits for pathway engineering, with applications in the food, energy and pharmaceutical sectors.

Polygenic Risk for Schizophrenia, Brain Structure and Environmental Risk in UK Biobank

Schizophrenia is a heritable neurodevelopmental disorder characterized by neuroanatomical changes in the brain but exactly how increased genetic burden for schizophrenia influences brain structure is unknown. Similarly, the impact of environmental risk factors for schizophrenia on brain structure is not fully understood. We investigated how genetic burden for schizophrenia (indexed by a polygenic risk score, PRS-SCZ) was associated with cortical thickness (CT), cortical surface area (SA), cortical volume (CV) and multiple subcortical structures within 18,147 White British ancestry participants from UK Biobank. We also explored whether environmental risk factors for schizophrenia (cannabis use, childhood trauma, low birth weight and Townsend social deprivation index) exacerbated the impact of PRS-SCZ on brain structure. We found that PRS-SCZ was significantly associated with lower CT in the frontal lobe, insula lobe, lateral orbitofrontal cortex, medial orbitofrontal cortex, posterior cingulate cortex and inferior frontal cortex, as well as reduced SA and CV in the supramarginal cortex and superior temporal cortex, but not with differences in subcortical volumes. When models included environmental risk factors as covariates, PRS-SCZ was only associated with lower SA/CV within the supramarginal cortex, superior temporal cortex and inferior frontal cortex. Moreover, no interactions were observed between PRS-SCZ and each of the environmental risk factors on brain structure. Overall, we identified brain structural correlates of PRS-SCZ predominantly within frontal and temporal regions. Some of these associations were independent of environmental risk factors, suggesting that they may represent biomarkers of genetic risk for schizophrenia.