Association of plasma gelsolin with frailty phenotype and mortality among octogenarian community-dwelling men : a cohort study

Background Biomarkers are needed for frailty, a common phenotype often associated with muscle loss in older people. Plasma gelsolin (pGSN) is a protein largely synthesized and secreted by skeletal muscle. Aims To investigate whether pGSN could be a biomarker of the frailty phenotype and predict mortality. Methods A homogenous cohort of males (born 1919-1934, baseline n = 3490) has been followed since the 1960s. In 2010/11, frailty phenotypes by modified Fried criteria were assessed. pGSN was measured in a convenience subset (n = 469, mean age 83) and re-measured in survivors (n = 127) in 2017. Mortality through December 31, 2018 was retrieved from national registers. Regression models were used for analyses. Results Of 469 males, 152 (32.4%) were robust, 284 (60.6%) prefrail, and 33 (7.0%) frail in 2010/11. There was a graded (p = 0.018) association between pGSN (mean 58.1 ug/mL, SD 9.3) and frailty. After multivariable adjustment, higher pGSN levels were associated with lower odds of having contemporaneous phenotypic prefrailty (OR per 1 SD 0.73, 95% CI 0.58-0.92) and frailty (OR per 1 SD 0.70, 95% CI 0.44-1.11). By 2018, 179 males (38.2%) had died, and higher baseline pGSN predicted a lower 7-year mortality rate (HR per 1 SD 0.85, 95% CI 0.72-1.00). pGSN concentrations in 2010/11 and 2017 were correlated (n = 127, r = 0.34, p < 0.001). Discussion Higher baseline pGSN concentrations were associated with a persistently robust phenotype and lower mortality rate over 7 years in a cohort of octogenarian males with high socioeconomic status and may be a promising laboratory biomarker for the development of a frailty phenotype.Peer reviewe

A stakeholder analysis of the perceived outcomes of developing and implementing England’s obesity strategy 2008–2011

Background International recommendations urge governments to implement population-based strategies to reduce the burden of obesity. This study assesses the development and implementation of the obesity strategy in England 2008–2011, Healthy Weight, Healthy Lives (HWHL). The aim was to identify if stakeholders perceived HWHL to have made any difference to the action to address obesity in England, with the ultimate objective of identifying insights that could inform the development and implementation of future obesity strategies in England and elsewhere. Methods Qualitative study using semi-structured interviews and thematic framework analysis. 40 stakeholders involved in the development and implementation of the obesity strategy were interviewed. Results Evidence from this study suggests that HWHL was perceived to have made a positive difference to efforts to address obesity in England. It was credited with creating political buy-in, engaging more stakeholders, stimulating and facilitating action, enhancing knowledge and changing attitudes. But it was reported to have failed to fully catalyse action across all government departments and sectors, or to develop adequate mechanisms for learning about the effectiveness of the different elements and actions in the Strategy. Key elements of the Strategy contributing towards to the perceived positive differences included its multi-faceted, inclusive nature; governance structures; monitoring programme to assess progress against national and local targets; child-focus; and funding. The development of the Strategy was said to be stimulated and aided by the prior synthesis of a critical mass of scientific evidence. Conclusions The English experience of HWHL lends support to the recommendations to develop population-based obesity strategies. It indicates that in order to stimulate comprehensive, inter-sectoral action, obesity strategies need to take a population-based, multi-faceted approach, be implemented through a clear governance structure, follow a systematic process of aligning goals, objectives and agendas between government departments and sectors with a stake in obesity, and have a clear system of reporting changes in obesity rates against a target. In order to design effective policies and to build the case for continued investment, obesity strategies also need to incorporate a national framework for learning and evaluation from the outset

Meta‐Analysis of Genome‐wide Linkage Studies in BMI and Obesity

Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI‐defined obesity using a nonparametric genome scan meta‐analysis. Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome‐wide logarithm of the odds (LOD) scores, non‐parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI‐defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Results: Bins at chromosome 13q13.2‐ q33.1, 12q23‐q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3‐22.3 were also observed for BMI‐defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1‐qter and 12p11.21‐q23 (p < 0.01). Conclusion: Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93663/1/oby.2007.269.pd

Whole-Exome Capture and Sequencing Identifies HEATR2 Mutation as a Cause of Primary Ciliary Dyskinesia

Motile cilia are essential components of the mucociliary escalator and are central to respiratory-tract host defenses. Abnormalities in these evolutionarily conserved organelles cause primary ciliary dyskinesia (PCD). Despite recent strides characterizing the ciliome and sensory ciliopathies through exploration of the phenotype-genotype associations in model organisms, the genetic bases of most cases of PCD remain elusive. We identified nine related subjects with PCD from geographically dispersed Amish communities and performed exome sequencing of two affected individuals and their unaffected parents. A single autosomal-recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function. Airway epithelial cells isolated from PCD-affected individuals had markedly reduced HEATR2 levels, absent dynein arms, and loss of ciliary beating. MicroRNA-mediated silencing of the orthologous gene in Chlamydomonas reinhardtii resulted in absent outer dynein arms, reduced flagellar beat frequency, and decreased cell velocity. These findings were recapitulated by small hairpin RNA-mediated knockdown of HEATR2 in airway epithelial cells from unaffected donors. Moreover, immunohistochemistry studies in human airway epithelial cells showed that HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly. The identification of HEATR2 contributes to the growing number of genes associated with PCD identified in both individuals and model organisms and shows that exome sequencing in family studies facilitates the discovery of novel disease-causing gene mutations

GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores

Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis;however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder;3,264 attempters and 5,500 nonattempters with bipolar disorder;and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R-2=0.25%), bipolar disorder (R-2=0.24%), and schizophrenia (R-2=0.40%). Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt

GWAS of Suicide Attempt in Psychiatric Disorders Identifies Association With Major Depression Polygenic Risk Scores

Objective: Over 90% of suicide attempters have a psychiatric diagnosis, however twin and family studies suggest that the genetic etiology of suicide attempt (SA) is partially distinct from that of the psychiatric disorders themselves. Here, we present the largest genome-wide association study (GWAS) on suicide attempt using major depressive disorder (MDD), bipolar disorder (BIP) and schizophrenia (SCZ) cohorts from the Psychiatric Genomics Consortium. Method: Samples comprise 1622 suicide attempters and 8786 non-attempters with MDD, 3264 attempters and 5500 non-attempters with BIP and 1683 attempters and 2946 non-attempters with SCZ. SA GWAS were performed by comparing attempters to non-attempters in each disorder followed by meta-analyses across disorders. Polygenic risk scoring was used to investigate the genetic relationship between SA and the psychiatric disorders. Results: Three genome-wide significant loci for SA were found: one associated with SA in MDD, one in BIP, and one in the meta-analysis of SA in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with SA in MDD (R2=0.25%, P=0.0006), BIP (R2=0.24%, P=0.0002) and SCZ (R2=0.40%, P=0.0006). Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size hold potential to robustly identify genetic associations and gain biological insights into the etiology of suicide attempt

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