Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome‐wide associations

Genome‐wide association studies (GWAS) using high‐density genotyping platforms offer an unbiased strategy to identify new candidate genes for osteoporosis. It is imperative to be able to clearly distinguish signal from noise by focusing on the best phenotype in a genetic study. We performed GWAS of multiple phenotypes associated with fractures [bone mineral density (BMD), bone quantitative ultrasound (QUS), bone geometry, and muscle mass] with approximately 433,000 single‐nucleotide polymorphisms (SNPs) and created a database of resulting associations. We performed analysis of GWAS data from 23 phenotypes by a novel modification of a block clustering algorithm followed by gene‐set enrichment analysis. A data matrix of standardized regression coefficients was partitioned along both axes—SNPs and phenotypes. Each partition represents a distinct cluster of SNPs that have similar effects over a particular set of phenotypes. Application of this method to our data shows several SNP‐phenotype connections. We found a strong cluster of association coefficients of high magnitude for 10 traits (BMD at several skeletal sites, ultrasound measures, cross‐sectional bone area, and section modulus of femoral neck and shaft). These clustered traits were highly genetically correlated. Gene‐set enrichment analyses indicated the augmentation of genes that cluster with the 10 osteoporosis‐related traits in pathways such as aldosterone signaling in epithelial cells, role of osteoblasts, osteoclasts, and chondrocytes in rheumatoid arthritis, and Parkinson signaling. In addition to several known candidate genes, we also identified PRKCH and SCNN1B as potential candidate genes for multiple bone traits. In conclusion, our mining of GWAS results revealed the similarity of association results between bone strength phenotypes that may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in identifying novel genes and pathways that underlie several correlated phenotypes, as well as in deciphering genetic and phenotypic modularity underlying osteoporosis risk. © 2011 American Society for Bone and Mineral Research.     

Interleukin-2 receptor antibody (basiliximab) for immunosuppressive induction therapy after liver transplantation: a protocol with early elimination of steroids and reduction of tacrolimus dosage.

A prospective evaluation was performed to study the potential benefits of the use of interleukin-2 receptor antibody (IL-2Rab) in the induction therapy with early elimination of steroid and reduction of tacrolimus dosage in liver transplant recipients among whom 94% had chronic hepatitis B infection. Thirty-one liver transplant recipients who underwent right-lobe live donor (n = 19) or cadaveric (n = 12) liver transplantation received IL-2Rab, basiliximab 20 mg intravenously within 6 hours of graft reperfusion and on postoperative day 4 (IL-2ab group). Two doses of steroid injection were given intraoperatively and on postoperative day 1. Postoperative immunosuppression was maintained with oral tacrolimus and mycophenolate mofetil without the use of steroids. The operative outcomes were compared with those of 49 patients who received standard immunosuppressive regimen consisting of tacrolimus and corticosteroid (steroid group). The overall postoperative morbidity and hospital stay were comparable between the 2 groups. There were significantly lower incidences of postoperative new-onset diabetes (0% vs 28%, P =.011), acute cellular rejection (6% vs 27%, P =.038), and cytomegalovirus (CMV) antigenemia (0% vs 18%, P =.011) in the IL-2Rab group compared with the steroid group. The blood cholesterol level at 6 months after transplantation was significantly lower in the IL-2Rab group (median, 4.0 vs 4.4 mmol/L, P =.007). On follow-up, none of the patients in the IL-2Rab group had hepatitis B viral breakthrough or hepatocellular carcinoma (HCC) recurrence, whereas 1 and 3 patients in the steroid group developed these complications, respectively. In conclusion, treatment of liver transplant recipients with IL-2Rab with early withdrawal of steroids and reduction of tacrolimus dosage is associated with lower incidences of postoperative new-onset diabetes, acute cellular rejection, and CMV antigenemia, as well as a lower serum cholesterol level. Further studies and long-term follow-up are required to document their potential benefits on hepatitis B and HCC recurrences.     

Genetic effect of MTHFR C677T polymorphism on the structural covariance network and white‐matter integrity in Alzheimer's disease

The 677 C to T transition in the MTHFR gene is a genetic determinant for hyperhomocysteinemia. We investigated whether this polymorphism modulates gray matter (GM) structural covariance networks independently of white‐matter integrity in patients with Alzheimer's disease (AD). GM structural covariance networks were constructed by 3D T1‐magnetic resonance imaging and seed‐based analysis. The patients were divided into two genotype groups: C homozygotes (n = 73) and T carriers (n = 62). Using diffusion tensor imaging and white‐matter parcellation, 11 fiber bundle integrities were compared between the two genotype groups. Cognitive test scores were the major outcome factors. The T carriers had higher homocysteine levels, lower posterior cingulate cortex GM volume, and more clusters in the dorsal medial lobe subsystem showing stronger covariance strength. Both posterior cingulate cortex seed and interconnected peak cluster volumes predicted cognitive test scores, especially in the T carriers. There were no between‐group differences in fiber tract diffusion parameters. The MTHFR 677T polymorphism modulates posterior cingulate cortex‐anchored structural covariance strength independently of white matter integrities. Hum Brain Mapp 38:3039–3051, 2017. © 2017 The Authors Human Brain Mapping Published Wiley by Periodicals, Inc.     

Comparison of donor scores in bilateral lung transplantation—A large single-center analysis

Objectifying donor lung quality is difficult and currently there is no consensus. Several donor scoring systems have been proposed in recent years. They all lack large-scale external validation and widespread acceptance. A retrospective evaluation of 2201 donor lungs offered to the lung transplant program at the Medical University of Vienna between January 2010 and June 2018 was performed. Five different lung donor scores were calculated for each offer (Oto, ET, MALT, UMN-DLQI, and ODSS). Prediction of organ utilization, 1-year graft survival, and long-term outcome were analyzed for each score. 1049 organs were rejected at the initial offer (group I), 209 lungs declined after procurement (group II), and 841 lungs accepted and transplanted (group III). The Oto score was superior in predicting acceptance of the initial offer (AUC: 0.795; CI: 0.776–0.815) and actual donor utilization (AUC: 0.660; CI: 0.618–0.701). Prediction of 1-year graft survival was best using the MALT score, Oto score, and UMN-DLQI. Stratification of early outcome by MALT was significant for length of mechanical ventilation (LMV), PGD3 rates, ICU stay and hospital stay, and in-hospital-mortality, respectively. To the best of our knowledge, this study is the largest validation analysis comparing currently available donor scores. The Oto score was superior in predicting organ utilization, and MALT score and UMN-DLQI for predicting outcome after lung transplantation.     

Association Between Total Cholesterol and 5 year Mortality in Patients with Carotid Artery Stenosis and Poststroke Functional Dependence

Background: Aggressive lipid-lowering treatment reduces the risk of cardiovascular events, but remains controversial in stroke patients. We investigate the influence of total cholesterol level on 5-year outcomes of ischemic stroke patients with high-grade internal carotid artery (ICA) stenosis and poststroke functional dependence.Methods: One-hundred and ninety-six acute ischemic stroke patients with high-grade ICA stenosis and modified Rankin Scale score ≥ 3 upon discharge were enrolled and prospectively observed for 5 years. Patients were divided into 2 groups according to total cholesterol level at admission: ≥200 mg/dL or <200 mg/dL. Demographic features, vascular risk factors, co-morbidities, and outcomes were compared between the 2 groups. Results: 117 (59.7%) patients had higher and 79 (40.3%) patients had lower total cholesterol levels. The prevalence of older age and atrial fibrillation was significantly higher in patients with lower total cholesterol; the prevalence of diabetes mellitus was higher in patients with higher total cholesterol. After adjusting for the established clinical predictors of adverse outcomes, the multivariate Cox regression revealed that lower total cholesterol level is a significant predictor of 5-year mortality (HR (hazard ratio)?=?1.88, 95% CI (confidence interval)?=?1.09-3.23, P?=?.023). Conclusions: Lower total cholesterol level is associated with increased risk of 5-year mortality in ischemic stroke patients with high-grade ICA stenosis and post-stroke functional dependence. Aggressive treatment of hyperlipidemia should be carefully considered in these patients although it could reduce the risk of atherosclerotic cardiovascular diseases and stroke recurrence in some stroke patients.     

The interleukin 10 promoter haplotype ACA and the long-form variant of the DRD4 uVNTR polymorphism are associated with vulnerability to schizophrenia

A total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin-10 (IL-10) promoter and DRD4 uVNTR polymorphisms. DRD4 long-form variants (namely, those with ≥ 5 repeats), homozygosity for the 4-repeat allele, and the IL-10 haplotype ACA were associated with schizophrenia, respectively. No obvious interactions among the potential polymorphisms were found, which suggests that IL-10 and DRD4 confer vulnerability to schizophrenia independently.     

Moderators and mediators among panic, agoraphobia symptoms, and suicidal ideation in patients with panic disorder

Objectives

The most important change of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) is the use of dimensional approach to assess the severity of symptoms across different diagnosis. There are 2 purposes in this study: the first purpose was to identify the proportion of outpatients with panic disorder who have suicidal ideation. The second aim was to examine the relationships among panic, agoraphobic symptoms, and suicidal ideation in patients with panic disorder, adjusting by age, social support, and alcohol use.

Methods

Sixty patients with panic disorder were recruited from outpatient psychiatric clinics in southern Taiwan. Suicidal ideation in the preceding 2 weeks was measured. The Panic and Agoraphobic Symptoms Checklist, Social Support Scale, Questionnaire for Adverse Effects of Medication for Panic Disorder, and Social Status Rating Scale were used to understand the severity of panic and agoraphobia, social support, drug adverse effects, and social status. Significant variables from the univariate analysis were included in a forward regression model. Then, we used structural equation modeling to fit the model.

Results

We found that 31.7% of outpatients with panic disorder had had suicidal ideation in the preceding 2 weeks. Multiple regression analysis showed that younger age, current alcohol use, more severe panic symptoms, and less social support were associated with suicidal ideation. In addition, the structural equation model illustrated the recursive model from panic to agoraphobia and suicidal ideation. Agoraphobia had no association with suicidal ideation. Panic symptom was a mediator to suicidal ideation but not agoraphobic symptoms.

Conclusions

A high proportion of patients with panic disorder had suicidal ideation. We found that panic symptoms, social support, age, and alcohol use affected suicide and could be identified. The 3-level model from panic to agoraphobia revealed that panic was a predictor of agoraphobia and agoraphobia was not a predictor of panic. This verified the evolution of the diagnostic view of the DSM. Panic symptom was a mediator to suicidal ideation. With the dimensional model in DSM-V, panic symptoms can be used as a marker for greater morbidity and severity.     

Glucocorticoid signaling and exercise-induced downregulation of the mineralocorticoid receptor in the induction of adult mouse dentate neurogenesis by treadmill running

Physical exercise is known to promote adult neurogenesis, although the underlying mechanisms remain unclear. Glucocorticoid (corticosterone in rodents) is a factor that is known to affect neurogenesis. As physical exercise modulates corticosterone secretion, we hypothesized that corticosterone signaling is involved in exercise-induced adult neurogenesis. We chose treadmill running (TR) to accurately define the intensity and duration of exercise. Our results showed that 5 weeks of TR increased the doublecortin (DCX)-positive neuronal progenitor cells (NPCs) in adult hippocampus and transiently increased the serum corticosterone level at the end of the TR protocol. This protocol reduced the levels of hippocampal mineralocorticoid receptor (MR); however, glucocorticoid receptor levels were unaltered. We then investigated whether reducing corticosterone levels by bilateral adrenalectomy (ADX) attenuated the TR-enhanced adult neurogenesis. Our results showed that ADX not only blocked the TR-induced downregulation of MR, but also reduced the number of TR-enhanced NPCs. In order to examine the role of MR downregulation in TR-induced adult neurogenesis, animals were treated repeatedly with a selective MR antagonist, spironolactone, for 3 weeks. The results revealed that spironolactone increased the number of spontaneously occurring and TR-induced NPC in the dentate area. Further analysis revealed that spironolactone treatment did not alter precursor cell proliferation, but increased the number of DCX-positive NPCs, suggesting that blockage of MR signaling either facilitates the differentiation of progenitor cells towards neurons and/or enhances the survival of NPCs. Taken together, the data indicated that induction of NPCs in the dentate area of adult hippocampus by TR is partly due to the downregulation of glucocorticoid/MR signaling, which subsequently enhances differentiation along a neuronal lineage and/or NPC survival.