Patients with paroxysmal nocturnal hemoglobinuria demonstrate a prothrombotic clotting phenotype which is improved by complement inhibition with eculizumab

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder, characterized by complement‐mediated intravascular hemolysis and thrombosis. The increased incidence of PNH‐driven thrombosis is still poorly understood, but unlike other thrombotic disorders, is thought to largely occur through complement‐mediated mechanisms. Treatment with a C5 inhibitor, eculizumab, has been shown to significantly reduce the number of thromboembolic events in these patients. Based on previously described links between changes in fibrin clot structure and thrombosis in other disorders, our aim was to investigate clot structure as a possible mechanism of thrombosis in patients with PNH and the anti‐thrombotic effects of eculizumab treatment on clot structure. Clot structure, fibrinogen levels and thrombin generation were examined in plasma samples from 82 patients from the National PNH Service in Leeds, UK. Untreated PNH patients were found to have increased levels of fibrinogen and thrombin generation, with subsequent prothrombotic changes in clot structure. No link was found between increasing disease severity and fibrinogen levels, thrombin generation, clot formation or structure. However, eculizumab treated patients showed decreased fibrinogen levels, thrombin generation and clot density, with increasing time spent on treatment augmenting these antithrombotic effects. These data suggest that PNH patients have a prothrombotic clot phenotype due to increased fibrinogen levels and thrombin generation, and that the antithrombotic effects of eculizumab are, in‐part, due to reductions in fibrinogen and thrombin generation with downstream effects on clot structure

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders

All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs

Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1−FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci

SSRI treatment decreases prolactin and hyperthermic responses to mCPP.

We studied the effect of 3 weeks treatment with the selective serotonin re-uptake inhibitor (SSRI), paroxetine (30 mg daily), on the neuroendocrine and hyperthermic responses to the 5-HT2C receptor agonist, m-chlorophenylpiperazine (mCPP) (0.05 mg/kg i.v.), in seven healthy volunteers. Following paroxetine treatment, both the prolactin and hyperthermic responses to mCPP were significantly attenuated. These data are consistent with experimental animal studies indicating that repeated SSRI treatment leads to a functional desensitisation of 5-HT2C receptors. This effect may be linked to the anxiolytic properties of SSRIs

Clomipramine enhances the cortisol response to 5-HTP: implications for the therapeutic role of 5-HT2 receptors.

We measured the cortisol response to the 5-HT precursor, 5-hydroxytryptophan, (5-HTP) in seven patients with major depression before and after 8 weeks treatment with the tricyclic antidepressant, clomipramine. The cortisol response to 5-HTP was significantly increased following clomipramine treatment, suggesting that clomipramine, like selective serotonin re-uptake inhibitors (SSRIs), enhances this 5-HT2 receptor mediated response. Because other tricyclic antidepressants do not increase 5-HTP-mediated cortisol release, it seems unlikely that enhancement of 5-HT2 receptor function is a critical mechanism for antidepressant action. However, facilitation of neurotransmission at 5-HT2 receptors could account for the efficacy of clomipramine and SSRIs in the treatment of obsessive compulsive disorder and also for their liability to cause orgasmic dysfunction

Is lateral bias anomalous in early-onset schizophrenia? Selected comparisons with normal populations.

The aim of this study was to investigate lateral bias in patients with early-onset schizophrenia. Hand, eye, and foot preferences and relative hand skill were examined in early-onset patients (n=44) and matched controls (n=39), and were compared with population estimates. Patients demonstrated a significant excess in mixed handedness (20.5% vs. 8.5%) relative to population estimates and reduced relative hand skill on a pegboard task compared with controls. Left eye preference was significantly less common in schizophrenic patients relative to population estimates. Crossed eye-hand and eye-foot preferences were not significantly increased in the patient group as a whole but were present, respectively, in four of nine and five of nine mixed-handed patients but in none of five mixed-handed controls. These findings are consistent with the view that lateralisation is anomalous in schizophrenia early in the course of illness

Serotonin transporter (5-HTT) promoter genotype may influence the prolactin response to clomipramine.

RATIONALE: A 44-base-pair insertion/deletion polymorphism in the promoter region of the human serotonin (5-HT) transporter (5-HTT) gene gives rise to a bi-allelic polymorphism designated long (l) and short (s). The s variant is associated with a lower expression of 5-HTT sites and a reduced efficiency of 5-HT reuptake. OBJECTIVE: The aim of the present study was to determine whether the increase in brain 5-HT function produced by acute 5-HT reuptake blockade is influenced by the 5-HTT promoter l/s polymorphism. METHODS: We measured the increase in plasma prolactin that follows acute administration of the tricyclic antidepressant clomipramine as an index of 5-HT neurotransmission in 14 healthy female subjects (7 with ss genotype and 7 with ll genotype) using a placebo-controlled crossover design. RESULTS: Clomipramine-induced prolactin release was significantly greater in subjects with the ll genotype. CONCLUSION: Our findings suggest that acute 5-HT reuptake blockade produces a greater increase in 5-HT neurotransmission in subjects with the ll genotype than in those with an ss genotype. These results are consistent with clinical data indicating that subjects with an ss genotype may have a poorer therapeutic response to selective serotonin reuptake inhibitor (SSRI) monotherapy