Investigating the relationship between DNA methylation age acceleration and risk factors for Alzheimer’s disease

This work was supported by a Alzheimer's Research UK Major Project grant (ARUK-PG2017B-10). Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team that includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, health-care assistants and nurses. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland, and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” [STRADL];104036/Z/14/Z). DNA methylation data collection was funded by the Wellcome Trust Strategic Award (10436/Z/14/Z). The research was conducted in the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1); funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. CCACE supports I.J.D. with some additional support from the Dementias Platform UK (MR/L015382/1). A.M.M. and H.C.W. have received support from the Sackler Institute.Peer reviewedPublisher PD

Chest Fat Quantification via CT Based on Standardized Anatomy Space in Adult Lung Transplant Candidates

Purpose Overweight and underweight conditions are considered relative contraindications to lung transplantation due to their association with excess mortality. Yet, recent work suggests that body mass index (BMI) does not accurately reflect adipose tissue mass in adults with advanced lung diseases. Alternative and more accurate measures of adiposity are needed. Chest fat estimation by routine computed tomography (CT) imaging may therefore be important for identifying high-risk lung transplant candidates. In this paper, an approach to chest fat quantification and quality assessment based on a recently formulated concept of standardized anatomic space (SAS) is presented. The goal of the paper is to seek answers to several key questions related to chest fat quantity and quality assessment based on a single slice CT (whether in the chest, abdomen, or thigh) versus a volumetric CT, which have not been addressed in the literature. Methods Unenhanced chest CT image data sets from 40 adult lung transplant candidates (age 58 ± 12 yrs and BMI 26.4 ± 4.3 kg/m2), 16 with chronic obstructive pulmonary disease (COPD), 16 with idiopathic pulmonary fibrosis (IPF), and the remainder with other conditions were analyzed together with a single slice acquired for each patient at the L5 vertebral level and mid-thigh level. The thoracic body region and the interface between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in the chest were consistently defined in all patients and delineated using Live Wire tools. The SAT and VAT components of chest were then segmented guided by this interface. The SAS approach was used to identify the corresponding anatomic slices in each chest CT study, and SAT and VAT areas in each slice as well as their whole volumes were quantified. Similarly, the SAT and VAT components were segmented in the abdomen and thigh slices. Key parameters of the attenuation (Hounsfield unit (HU) distributions) were determined from each chest slice and from the whole chest volume separately for SAT and VAT components. The same parameters were also computed from the single abdominal and thigh slices. The ability of the slice at each anatomic location in the chest (and abdomen and thigh) to act as a marker of the measures derived from the whole chest volume was assessed via Pearson correlation coefficient (PCC) analysis. Results The SAS approach correctly identified slice locations in different subjects in terms of vertebral levels. PCC between chest fat volume and chest slice fat area was maximal at the T8 level for SAT (0.97) and at the T7 level for VAT (0.86), and was modest between chest fat volume and abdominal slice fat area for SAT and VAT (0.73 and 0.75, respectively). However, correlation was weak for chest fat volume and thigh slice fat area for SAT and VAT (0.52 and 0.37, respectively), and for chest fat volume for SAT and VAT and BMI (0.65 and 0.28, respectively). These same single slice locations with maximal PCC were found for SAT and VAT within both COPD and IPF groups. Most of the attenuation properties derived from the whole chest volume and single best chest slice for VAT (but not for SAT) were significantly different between COPD and IPF groups. Conclusions This study demonstrates a new way of optimally selecting slices whose measurements may be used as markers of similar measurements made on the whole chest volume. The results suggest that one or two slices imaged at T7 and T8 vertebral levels may be enough to estimate reliably the total SAT and VAT components of chest fat and the quality of chest fat as determined by attenuation distributions in the entire chest volume

Common Genetic Variants Explain the Majority of the Correlation Between Height and Intelligence : The Generation Scotland Study

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Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant

RATIONALE: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. OBJECTIVES: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. METHODS: Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. MEASUREMENTS AND MAIN RESULTS: A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination. CONCLUSIONS: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination

Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank

Background: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants. Methods: In the present analysis, three cohort studies (ntotal = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions. Results: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer’s disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10-7), was the butyrylcholinesterase (BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognitive ability merits further investigation. Conclusions: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect

Codimension-Three Bundle Singularities in F-Theory

We study new nonperturbative phenomena in N=1 heterotic string vacua corresponding to pointlike bundle singularities in codimension three. These degenerations result in new four-dimensional infrared physics characterized by light solitonic states whose origin is explained in the dual F-theory model. We also show that such phenomena appear generically in $E_7 \to E_6$ Higgsing and describe in detail the corresponding bundle transition.Comment: 24 pages, 1 figure, uses xypic; a reference adde

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing:a population-based study

Background&lt;p&gt;&lt;/p&gt; Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.&lt;p&gt;&lt;/p&gt; Methods&lt;p&gt;&lt;/p&gt; We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.&lt;p&gt;&lt;/p&gt; Results&lt;p&gt;&lt;/p&gt; Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.&lt;p&gt;&lt;/p&gt; Conclusions&lt;p&gt;&lt;/p&gt; We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis