Epidemiology and genetic architecture of blood pressure: a family based study of Generation Scotland

Hypertension is a major risk factor for cardiovascular disease and mortality, and a growing global public health concern, with up to one-third of the world’s population affected. Despite the vast amount of evidence for the benefits of blood pressure (BP) lowering accumulated to date, elevated BP is still the leading risk factor for disease and disability worldwide. It is well established that hypertension and BP are common complex traits, where multiple genetic and environmental factors contribute to BP variation. Furthermore, family and twin studies confirmed the genetic component of BP, with a heritability estimate in the range of 30-50%. Contemporary genomic tools enabling the genotyping of millions of genetic variants across the human genome in an efficient, reliable, and cost-effective manner, has transformed hypertension genetics research. This is accompanied by the presence of international consortia that have offered unprecedentedly large sample sizes for genome-wide association studies (GWASs). While GWAS for hypertension and BP have identified more than 60 loci, variants in these loci are associated with modest effects on BP and in aggregate can explain less than 3% of the variance in BP. The aims of this thesis are to study the genetic and environmental factors that influence BP and hypertension traits in the Scottish population, by performing several genetic epidemiological analyses. In the first part of this thesis, it aims to study the burden of hypertension in the Scottish population, along with assessing the familial aggregation and heritialbity of BP and hypertension traits. In the second part, it aims to validate the association of common SNPs reported in the large GWAS and to estimate the variance explained by these variants. In this thesis, comprehensive genetic epidemiology analyses were performed on Generation Scotland: Scottish Family Health Study (GS:SFHS), one of the largest population-based family design studies. The availability of clinical, biological samples, self-reported information, and medical records for study participants has allowed several assessments to be performed to evaluate factors that influence BP variation in the Scottish population. Of the 20,753 subjects genotyped in the study, a total of 18,470 individuals (grouped into 7,025 extended families) passed the stringent quality control (QC) criteria and were available for all subsequent analysis. Based on the BP-lowering treatment exposure sources, subjects were further classified into two groups. First, subjects with both a self-reported medications (SRMs) history and electronic-prescription records (EPRs; n =12,347); second, all the subjects with at least one medication history source (n =18,470). In the first group, the analysis showed a good concordance between SRMs and EPRs (kappa =71%), indicating that SRMs can be used as a surrogate to assess the exposure to BP-lowering medication in GS:SFHS participants. Although both sources suffer from some limitations, SRMs can be considered the best available source to estimate the drug exposure history in those without EPRs. The prevalence of hypertension was 40.8% with higher prevalence in men (46.3%) compared to women (35.8%). The prevalence of awareness, treatment and controlled hypertension as defined by the study definition were 25.3%, 31.2%, and 54.3%, respectively. These findings are lower than similar reported studies in other populations, with the exception of controlled hypertension prevalence, which can be considered better than other populations. Odds of hypertension were higher in men, obese or overweight individuals, people with a parental history of hypertension, and those living in the most deprived area of Scotland. On the other hand, deprivation was associated with higher odds of treatment, awareness and controlled hypertension, suggesting that people living in the most deprived area may have been receiving better quality of care, or have higher comorbidity levels requiring greater engagement with doctors. These findings highlight the need for further work to improve hypertension management in Scotland. The family design of GS:SFHS has allowed family-based analysis to be performed to assess the familial aggregation and heritability of BP and hypertension traits. The familial correlation of BP traits ranged from 0.07 to 0.20, and from 0.18 to 0.34 for parent-offspring pairs and sibling pairs, respectively. A higher correlation of BP traits was observed among first-degree relatives than other types of relative pairs. A variance-component model that was adjusted for sex, body mass index (BMI), age, and age-squared was used to estimate heritability of BP traits, which ranged from 24% to 32% with pulse pressure (PP) having the lowest estimates. The genetic correlation between BP traits showed a high correlation between systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) (G: 81% to 94%), but lower correlations with PP (G: 22% to 78%). The sibling recurrence risk ratio (λS) for hypertension and treatment were calculated as 1.60 and 2.04 respectively. These findings confirm the genetic components of BP traits in GS:SFHS, and justify further work to investigate genetic determinants of BP. Genetic variants reported in the recent large GWAS of BP traits were selected for genotyping in GS:SFHS using a custom designed TaqMan® OpenArray®. The genotyping plate included 44 single nucleotide polymorphisms (SNPs) that have been previously reported to be associated with BP or hypertension at genome-wide significance level. A linear mixed model that is adjusted for age, age-squared, sex, and BMI was used to test for the association between the genetic variants and BP traits. Of the 43 variants that passed the QC, 11 variants showed statistically significant association with at least one BP trait. The phenotypic variance explained by these variant for the four BP traits were 1.4%, 1.5%, 1.6%, and 0.8% for SBP, DBP, MAP, and PP, respectively. The association of genetic risk score (GRS) that were constructed from selected variants has showed a positive association with BP level and hypertension prevalence, with an average effect of one mmHg increase with each 0.80 unit increases in the GRS across the different BP traits. The impact of BP-lowering medication on the genetic association study for BP traits has been established, with typical practice of adding a fixed value (i.e. 15/10 mmHg) to the measured BP values to adjust for BP treatment. Using the subset of participants with the two treatment exposure sources (i.e. SRMs and EPRs), the influence of using either source to justify the addition of fixed values in SNP association signal was analysed. BP phenotypes derived from EPRs were considered the true phenotypes, and those derived from SRMs were considered less accurate, with some phenotypic noise. Comparing SNPs association signals between the four BP traits in the two model derived from the different adjustments showed that MAP was the least impacted by the phenotypic noise. This was suggested by identifying the same overlapped significant SNPs for the two models in the case of MAP, while other BP traits had some discrepancy between the two source

Risk of neuropsychiatric adverse effects of lipid-lowering drugs: a Mendelian randomization study

Background: Recent studies have highlighted the possible risk of neuropsychiatric adverse effects during treatment with lipid-lowering medications. However, there are still controversies that require a novel genetic-based approach to verify whether the impact of lipid-lowering drug treatment results in neuropsychiatric troubles including insomnia, depression, and neuroticism. Thus, we applied Mendelian randomization to assess any potential neuropsychiatric adverse effects of conventional lipid-lowering drugs such as statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and ezetimibe. Methods: A 2-sample Mendelian randomization study was conducted based on summary statistics from genome-wide association studies for lipids, insomnia, depression, and neuroticism. Single-nucleotide polymorphisms located in or near drug target genes of HMGCR, PCSK9, and NPC1L1 were used as proxies for statins, PCSK9 inhibitors, and ezetimibe therapy, respectively. To assess the validity of the genetic risk score, their associations with coronary artery disease were used as a positive control. Results: The Mendelian randomization analysis showed a statistically significant (P <.004) increased risk of depression after correcting for multiple testing with both statins (odds ratio=1.15, 95% CI: 1.04–1.19) and PCSK9 inhibitor treatment (odds ratio =1.19, 95%CI: 1.1–1.29). The risk of neuroticism was slightly reduced with statin therapy (odds ratio=0.9, 95%CI: 0.83–0.97). No significant adverse effects were associated with ezetimibe treatment. As expected, the 3 medications significantly reduced the risk of coronary artery disease. Conclusion: Using a genetic-based approach, this study showed an increased risk of depression during statin and PCSK9 inhibitor therapy while their association with insomnia risk was not significant

Energy dissipation and geometry effects over stepped spillways

The energy dissipation process is the major significant point in the designof hydraulic structure. The dissipation of high energy on stepped weirsprevents any damage in the weir itself and channels the energy ownstream to reduce the stilling basin size. In this study, four physical models are used to evaluate the impact of adding end sills that have a quarter circle shape at step edges. The amount of energy loss on weirs under different flow regimes is investigated by experimental work. Stepped weirs have a suitable number of steps and two different ratios of the width to height (2.22, and 2.40). The scale of the physical models is 20:1. The outcomes of the dimensional analyses refer to the critical depth for flow in weirs to the height of step yc/h, the end sill radius, and the number of steps N are more effective parameters than others inthe energy loss process. Moreover, for small values of yc/h, the energydissipation is the greatest. Any increase in yc/h leads to a decrease in theenergy dissipation, while the energy dissipation increases with the number of steps (N)

The Effect of Using Glass Powder Filler on Hot Asphalt Concrete Mixtures Properties

The early use of asphalt for road and street construction began in the late 1800s, and grew rapidly with the emerging automobile industry. Since that time, asphalt technology has made strides such that today the equipment, techniques and materials used to build asphalt pavement structures are highly sophisticated. Waste glass has been used in highway construction as an aggregate substitute in hot mix asphalt paving. Many countries have recently incorporated glass into their roadway specifications, which had encouraged greater use of the material. While the use of waste glass as filler in hot mix asphalt is still not widely experimented. In this research glass powder is proposed as an alternative to traditional lime stone powder (Gubraa) and ordinary Portland cement fillers in hot asphalt mixtures. Where, the effect of using waste glass powder as mineral filler on Marshall Properties of hot asphalt concrete mixtures is investigated. Nine mixtures with three types of fillers (lime stone powder, ordinary Portland cement and glass powder) and three filler contents (4%, 7% and 10% by weight of total aggregate) are investigated. The main outcome of this research is the possibility of using glass powder as filler in hot asphalt concrete mixtures. The optimum glass powder content is 7%. Where it is found that using of glass powder as filler with such replacement leading to produce asphalt mixture with higher stability (% of increase up to 13%), lower flow (% of decrease up to 39%) and lower density (% of decrease up to 10%) comparing to corresponding ordinary Portland cement or lime stone powder mixtures

Effects of dietary L-carnitine supplementation on growth performance and survival rate in common carp (Cyprinus carpio Linneaus 1758)

The aim of present study (60 days) was to evaluate the effect of dietary L-carnitine on growth performance and survival rate of Common Carp (Cyprinus carpio) via supplementation with Biomar. According to body length and weight, 180 common carp (average weight 13.21±2.5g) were divided into 4 groups (three replicates for each group). The L-carnitine was used in three concentrations 500 (T1), 1500 (T2) and 2500 (T3) mg/Kg-1 of diet (Biomar). The common carp in experimental treatments were fed of the three levels of L-carnitine with 5 percent body weight (3 times a day). The fish in control treatment was fed on not supplemented Biomar. The growth factors of fishes fed on L-carnitine were compared to those fishes in control treatment that fed of unsupplemented Biomar. The results clearly showed that animal fed the L-carnitine had significantly increased final body weight in comparison to control treatment. The maximum of final body weight (FBW) and Specific growth rate (SGR) were observed in treatment of T3 (P>0.05) followed by T2. There were no significantly different between T1 and control group in this compare (P>0.05) however T1 showed better result in grow performance than control group. Also in survival rate the treatments had no significantly different to each other (P>0.05)

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

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