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Sökning: WFRF:(Tyrrell Jessica)

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1.
  • Erzurumluoglu, A. Mesut, et al. (författare)
  • Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
  • 2020
  • Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
  • Tidskriftsartikel (refereegranskat)abstract
    • Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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2.
  • Beaumont, Robin N, et al. (författare)
  • Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
  • 2018
  • Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 1460-2083 .- 0964-6906. ; 27:4, s. 742-756
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
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3.
  • Heald, Adrian H., et al. (författare)
  • Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile
  • 2021
  • Ingår i: Diabetic Medicine. - : John Wiley & Sons. - 0742-3071 .- 1464-5491. ; 38:9
  • Tidskriftsartikel (refereegranskat)abstract
    • AimsChange in weight, HbA1c, lipids, blood pressure and cardiometabolic events over time is variable in individuals with type 2 diabetes. We hypothesized that people with a genetic predisposition to a more favourable adiposity distribution could have a less severe clinical course/progression.MethodsWe involved people with type 2 diabetes from two UK‐based cohorts: 11,914 individuals with GP follow‐up data from the UK Biobank and 723 from Salford. We generated a ‘favourable adiposity’ genetic score and conducted cross‐sectional and longitudinal studies to test its association with weight, BMI, lipids, blood pressure, medication use and risk of myocardial infarction and stroke using 15 follow‐up time points with 1‐year intervals.ResultsThe ‘favourable adiposity’ genetic score was cross‐sectionally associated with higher weight (effect size per 1 standard deviation higher genetic score: 0.91kg [0.59,1.23]) and BMI (0.30kg/m2 [0.19,0.40]), but higher high‐density lipoprotein (0.02mmol/L [0.01,0.02]) and lower triglycerides (‐0.04mmol/L [‐0.07,‐0.02]) in the UK Biobank at baseline, and this pattern of association was consistent across follow‐up.There was a trend for participants with higher ‘favourable adiposity’ genetic score to have lower risk of myocardial infarction and/or stroke (odds ratio 0.79 [0.62,1.00]) compared to those with lower score. A one standard deviation higher score was associated with lower odds of using lipid‐lowering (0.91 [0.86,0.97]) and anti‐hypertensive medication (0.95 [0.91,0.99]).ConclusionsIn individuals with type 2 diabetes, having more ‘favourable adiposity’ alleles is associated with a marginally better lipid profile long‐term and having lower odds of requiring lipid‐lowering or anti‐hypertensive medication in spite of relatively higher adiposity.
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4.
  • Ji, Yingjie, et al. (författare)
  • Genome-wide and abdominal MRI data provide evidence that a genetically determined favorable adiposity phenotype is characterized by lower ectopic liver fat and lower risk of type 2 diabetes, heart disease, and hypertension
  • 2019
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:1, s. 207-219
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.
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5.
  • Loginovic, Pavel, et al. (författare)
  • Applying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis
  • 2024
  • Ingår i: Nature Communications. - 2041-1723. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Optic neuritis (ON) is associated with numerous immune-mediated inflammatory diseases, but 50% patients are ultimately diagnosed with multiple sclerosis (MS). Differentiating MS-ON from non-MS-ON acutely is challenging but important; non-MS ON often requires urgent immunosuppression to preserve vision. Using data from the United Kingdom Biobank we showed that combining an MS-genetic risk score (GRS) with demographic risk factors (age, sex) significantly improved MS prediction in undifferentiated ON; one standard deviation of MS-GRS increased the Hazard of MS 1.3-fold (95% confidence interval 1.07–1.55, P < 0.01). Participants stratified into quartiles of predicted risk developed incident MS at rates varying from 4% (95%CI 0.5–7%, lowest risk quartile) to 41% (95%CI 33–49%, highest risk quartile). The model replicated across two cohorts (Geisinger, USA, and FinnGen, Finland). This study indicates that a combined model might enhance individual MS risk stratification, paving the way for precision-based ON treatment and earlier MS disease-modifying therapy.
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6.
  • Middeldorp, Christel M., et al. (författare)
  • The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects
  • 2019
  • Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:3, s. 279-300
  • Tidskriftsartikel (refereegranskat)abstract
    • The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
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7.
  • Plymale, Andrew E., et al. (författare)
  • Niche Partitioning of Microbial Communities at an Ancient Vitrified Hillfort : Implications for Vitrified Radioactive Waste Disposal
  • 2021
  • Ingår i: Geomicrobiology Journal. - : Taylor & Francis. - 0149-0451 .- 1521-0529. ; 38:1, s. 36-56
  • Tidskriftsartikel (refereegranskat)abstract
    • Because microbes cannot be eliminated from radioactive waste disposal facilities, the consequences of bio-colonization must be understood. At a pre-Viking era vitrified hillfort, Broborg, Sweden, anthropogenic glass has been subjected to bio-colonization for over 1,500 years. Broborg is used as a habitat analogue for disposed radioactive waste glass to inform how microbial processes might influence long-term glass durability. Electron microscopy and DNA sequencing of surficial material from the Broborg vitrified wall, adjacent soil, and general topsoil show that the ancient glass supports a niche microbial community of bacteria, fungi, and protists potentially involved in glass alteration. Communities associated with the vitrified wall are distinct and less diverse than soil communities. The vitrified niche of the wall and adjacent soil are dominated by lichens, lichen-associated microbes, and other epilithic, endolithic, and epigeic organisms. These organisms exhibit potential bio-corrosive properties, including silicate dissolution, extraction of essential elements, and secretion of geochemically reactive organic acids, that could be detrimental to glass durability. However, long-term biofilms can also possess a homeostatic function that could limit glass alteration. This study documents potential impacts that microbial colonization and niche partitioning can have on glass alteration, and subsequent release of radionuclides from a disposal facility for vitrified radioactive waste.
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8.
  • Schafmayer, Clemens, et al. (författare)
  • Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms
  • 2019
  • Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 68:5, s. 854-865
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. Design Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. Results We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p< 0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3x10-10 and 0.002 (OR allelic = 1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). Conclusion I n silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
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9.
  • Tyrrell, Jessica, et al. (författare)
  • Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.
  • 2016
  • Ingår i: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 315:11, s. 1129-40
  • Tidskriftsartikel (refereegranskat)abstract
    • Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.Offspring birth weight from 18 studies.Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
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10.
  • Tyrrell, Jessica, et al. (författare)
  • Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight.
  • 2012
  • Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 21:24, s. 5344-5358
  • Tidskriftsartikel (refereegranskat)abstract
    • Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: -4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.
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