Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs.Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.Molecular Epidemiolog

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Just say no (to stereotyping): Effects of training in the negation of stereotypic associations on stereotype activation

Item does not contain fulltextThe primary aim of the present research was to examine the effect of training in negating stereotype associations on stereotype activation. Across 3 studies, participants received practice in negating stereotypes related to skinhead and racial categories. The subsequent automatic activation of stereotypes was measured using either a primed Stroop task (Studies I and 2) or a person categorization task (Study 3). The results demonstrate that when receiving no training or training in a nontarget category stereotype, participants exhibited spontaneous stereotype activation. After receiving an extensive amount of training related to a specific category, however, participants demonstrated reduced stereotype activation. The results from the training task provide further evidence for the impact of practice on participants' proficiency in negating stereotypes

Dynamic aortic changes in patients with thoracic aortic aneurysms evaluated with electrocardiography-triggered computed tomographic angiography before and after thoracic endovascular aneurysm repair: preliminary results.

Item does not contain fulltextThe purpose of this study was to utilize dynamic computed tomographic angiography (CTA) on pre- and postoperative thoracic endovascular aneurysm repair (TEVAR) patients to characterize cardiac pulsatility-induced aortic motion on essential TEVAR proximal sealing zones and to study the influence of endograft placement. Six pre- and six postoperative dynamic CTA studies were obtained in six patients with thoracic aortic aneurysms (TAAs) undergoing TEVAR. Data were acquired using a retrospective electrocardiography-triggered dynamic CTA scan, with eight reconstructed phases over the cardiac cycle. Scans were acquired during a single breath hold. Multiplanar reconstructions were made perpendicular to the aorta at five surgically relevant anatomical thoracic landmarks: 1 cm proximal to the innominate trunk, 1 cm proximal and 1 cm distal to the left subclavian artery, and 1 cm proximal and 3 cm distal to the proximal end of the stent. After segmentation of the aortic lumen in the images, diameter change and area change over the cardiac cycle were measured. Diameter change was measured through the center of mass of the aortic lumen, and the average change over 180 axis is presented. We found significant distention of the thoracic aortic arch and descending thoracic aorta during the cardiac cycle before and after TEVAR. Distention ranged 3-12% in diameter and 2-20% in area. This distention was preserved after TEVAR. Patients with TAA experience aortic diameter and area changes during the cardiac cycle. The magnitude, and hence the clinical importance, of this aortic distention varies among patients. After stent-graft placement, aortic distention throughout the cardiac cycle is preserved. This may have major implications for correct sizing of the endograft as well as for stent-graft design and durability as the forces on the stents may be much larger after implantation than initially anticipated by stent manufacturers