We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10−11) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10−9), ANK3 (rs10994359, P = 2.5 × 10−8) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10−9).

Objective To determine the efficacy of anakinra (recombinant interleukin-1 receptor antagonist) in improving 28-day survival in sepsis patients with features of macrophage activation syndrome (MAS). Despite equivocal results in sepsis trials, anakinra is effective in treating MAS, a similar entity with fever, disseminated intravascular coagulation (DIC), hepatobiliary dysfunction (HBD), cytopenias, and hyperferritinemia. Hence, sepsis patients with MAS features may benefit from IL-1 receptor blockade. Design Re-analysis of de-identified data from the phase III randomized interleukin-1 receptor antagonist trial in severe sepsis (Opal, et. al. Crit Care Med. 1997 Jul;25(7):1115–24). Setting Multi-center study recruiting through 91 centers from 11 countries in Europe and North America. Participants Sepsis patients with MODS and/or shock (original study) were re-grouped based on presence or absence of concurrent HBD and DIC as features of MAS (HBD/DIC group). The “non-HBD/DIC” group included patients with only HBD, only DIC or neither. Intervention Treatment with anakinra or placebo. Main Outcome(s) and Measure(s) 28-day mortality. Statistical analysis descriptive statistics, chi-square, ANOVA, logistic and Cox regression. Results Data were available for 763 adults from the original study cohort, randomized to receive either anakinra or placebo. Concurrent HBD/DIC was noted in 43 patients (5.6% of total, ages 18–75; 47% women). The 28-day survival was similar in both anakinra and placebo-treated non-HBD/DIC patients (71.4% vs. 70.8%, p=.88). Treatment with anakinra was associated with significant improvement in the 28-day survival rate in HBD/DIC patients (65.4% anakinra vs. 35.3% placebo), with HR for death 0.28 (0.11–0.71, p = 0.0071) for the treatment group in Cox regression. Conclusions and Relevance In this subgroup analysis, IL-1 receptor blockade was associated with significant improvement in survival of patients with sepsis and concurrent HBD/DIC. A prospective randomized trial using features of MAS for mortality risk stratification should be undertaken to confirm the role of IL-1 blockage.

Acute kidney injury (AKI) is associated with progression to advanced chronic kidney disease (CKD). We tested whether patients who survive AKI and are at higher risk for CKD progression can be identified during their hospital admission, thus providing opportunities to intervene. This was assessed in patients in the Department of Veterans Affairs Healthcare System hospitalized with a primary diagnosis indicating AKI (ICD9 codes 584.xx). In the exploratory phase, three multivariate prediction models for progression to stage 4 CKD were developed. In the confirmatory phase, the models were validated in 11,589 patients admitted for myocardial infarction or pneumonia during the same time frame that had RIFLE codes R, I, or F and complete data for all predictor variables. Of the 5351 patients in the AKI group, 728 entered stage 4 CKD after hospitalization. Models 1, 2, and 3 were all significant with ‘c' statistics of 0.82, 0.81, and 0.77, respectively. In model validation, all three were highly significant when tested in the confirmatory patients, with moderate to large effect sizes and good predictive accuracy (‘c' 0.81–0.82). Patients with AKI who required dialysis and then recovered were at especially high risk for progression to CKD. Hence, the severity of AKI is a robust predictor of progression to CKD.

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined GWAS of 19,779 BP and SCZ cases versus 19,423 controls, in addition to a direct comparison GWAS of 7,129 SCZ cases versus 9,252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1, MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.

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We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein–coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.

Background and objectives CKD is a global public health problem with significant mortality and morbidity.Design, setting, participants, & measurements We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-a, TGF-b, high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants.Results Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of $50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-a and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P,0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P,0.01), and TNF-a (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P,0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P,0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P,0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P,0.001), and TNF-a (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P,0.001) with outcome were attenuated but remained significant.Conclusions Elevated plasma levels of fibrinogen and TNF-a and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.

When patients develop acute kidney injury, a small fraction of them will develop end-stage renal disease later. The severity of renal impairment in the remaining patients is uncertain because studies have not carefully examined renal function over time or the precise timing of entry into a late stage of chronic kidney disease. To determine these factors, we used a United States Department of Veterans Affairs database to ascertain long-term renal function in 113,272 patients. Of these, 44,377 had established chronic kidney disease and were analyzed separately. A cohort of 63,491 patients was hospitalized for acute myocardial infarction or pneumonia and designated as controls. The remaining 5,404 patients had diagnostic codes indicating acute renal failure or acute tubular necrosis. Serum creatinine, estimated glomerular filtration rates, and dates of death over a 75-month period were followed. Renal function deteriorated over time in all groups, but with significantly greater severity in those who had acute renal failure and acute tubular necrosis compared to controls. Patients with acute kidney injury, especially those with acute tubular necrosis, were more likely than controls to enter stage 4 chronic kidney disease, but this entry time was similar to that of patients who initially had chronic kidney disease. The risk of death was elevated in those with acute kidney injury and chronic kidney disease compared to controls after accounting for covariates. We found that patients who had an episode of acute tubular necrosis were at high risk for the development of stage 4 disease and had a reduced survival time when compared to control patients.