Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis

Background: Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS. Methods: We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls. Results: In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24–1.52, p = 6.9 × 10−10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31–1.79) compared to those with CAD (OR 1.27; 95%CI 1.12–1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88–0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27–1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95–1.02). Conclusions: Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS

Political Ideology and Stigmatizing Attitudes Toward Depression: The Swedish Case

Background: Stigmatizing attitudes toward persons with mental disorders is a well-established and global phenomenon often leading to discrimination and social exclusion. Although previous research in the United States showed that conservative ideology has been related to stigmatizing attitudes toward mental disorders, there is reason to believe that this mechanism plays a different role in the context of a universal welfare state with a multi-party system such as Sweden. Furthermore, “mental disorders” may signify severe psychotic disorders, which may evoke more negative attitudes. This suggests the importance of specific studies focusing on the more common phenomenon of depression. This paper investigates the relationship between political ideology and stigmatizing attitudes toward depression in Sweden.Methods: This study is part of the New Ways research program. Data were collected by the Laboratory of Opinion Research (LORE) at the University of Gothenburg in 2014 (N = 3246). Independent variables were political ideology and party affiliation. The dependent variable was the Depression Stigma Scale (DSS). Data were analyzed with linear regression analyses and analyses of variance.Results: More conservative ideology (B = 0.68, standard error [SE] = 0.04, P < .001) and more conservative party affiliation (F(8 2920) = 38.45, P < .001) showed more stigmatizing attitudes toward depression. Item-level analyses revealed a difference where the supporters of the conservative party differed (P < .05) from supporters of the liberal party, with a higher proportion agreeing that “people could snap out of ” depression if they wanted to; the populist right-wing party differed from the conservative party with a higher proportion agreeing on items displaying people with depression as “dangerous” and “unpredictable.” Even self-stigma was highest among the populist right-wing party with 22.3% agreeing that “if I had depression I wouldn’t tell....”Conclusion: Political ideology was associated with stigmatizing attitudes toward depression in Sweden. The results also confirm the need to distinguish between different forms of conservatism by observing social distance as being a more important driver among voters for the populist right-wing party compared with personal agency and responsibility among voters for the more traditional conservative party

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.National Institutes of HealthVoRSUNY DownstatePsychiatry and Behavioral SciencesInstitute for Genomics in HealthN/

Compensating distortion effects in repeated measurements under non-stationary conditions

In this paper a compensation technique is presented for applications using repeated measurements under moderate non-stationary measurement conditions. The assumption is that the measurement conditions are stationary during a single repeated measurement but non-stationary over the entire measurement time. The objective with repeated measurements is often to retrieve an estimate of the (noise reduced) signal and its uncertainties. In order to obtain accurate estimates of these two quantities, stationary measurement conditions must be guaranteed under the measurement time. A condition that in many situations is difficult to achieve, e.g., during long measurement times or in a rapidly changing environment. The proposed method compensates for linear dynamic changes during the measurement time, where the dynamical changes, the underlying signal waveform and the noise covariance are considered unknown. The theoretical effect of moderate non-stationary conditions on repeated measurements is analyzed and experimentally validated. Estimation results using the proposed technique are presented for repeated ultrasonic measurements under non-stationary temperature conditions. The results show accurate signal estimation and noise characterization with uncorrelated normally distributed residuals, in contrast to standard synchronization techniques</p