Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Sustained Release of IL-2 Using an Injectable Hydrogel Prevents Autoimmune Diabetes

ABSTRACT Interleukin 2 (IL-2) is a promising therapy for autoimmune type 1 diabetes (T1D), but the short half-life in vivo (less than 6 minutes) limits effective tissue exposure to IL-2. Tissue exposure is required for the tolerogenic effects of IL-2. We have developed an injectable hydrogel that incorporates heparin polymers to enable the sustained release of IL-2. This platform uses clinical grade and commercially available materials, including collagen, hyaluronan, and heparin, to deliver IL-2 by slowly degrading and releasing IL-2 over a two-week period in vivo . We find that heparin potentiates the activity of IL-2 and IL-2-mediated expansion of Foxp3+ regulatory T cell (Treg). Hydrogel-mediated IL-2 release showed a reduction of CD4+ and CD8+ T cells and an increase of FoxP3+ Treg in the lymph nodes of injected mice. Moreover, in the Non-Obese Diabetic (NOD) mouse model of T1D once-weekly administration of IL-2 hydrogels prevented diabetes onset as efficiently as 3x weekly repeated injections of soluble IL-2. Together these data suggest that heparin-containing hydrogels may have benefit in delivering low-dose IL-2 and promoting immune tolerance in autoimmune diabetes

Weekly injection of IL-2 using an injectable hydrogel reduces autoimmune diabetes incidence in NOD mice

IL-2 injections are a promising therapy for autoimmune type 1 diabetes but the short half-life of this cytokine in vivo limits effective tissue exposure and necessitates frequent injections. Here we have investigated whether an injectable hydrogel could be used to promote prolonged IL-2 release in vivo. Capitalising on the IL-2-binding capabilities of heparin, an injectable hydrogel incorporating clinical-grade heparin, collagen and hyaluronan polymers was used to deliver IL-2. The IL-2-release kinetics and in vivo stability of this material were examined. The ability of soluble IL-2 vs hydrogel-mediated IL-2 injections to prevent autoimmune diabetes in the NOD mouse model of type 1 diabetes were compared. We observed in vitro that the hydrogel released IL-2 over a 12-day time frame and that injected hydrogel likewise persisted 12 days in vivo. Notably, heparin binding potentiates the activity of IL-2 and enhances IL-2- and TGFβ-mediated expansion of forkhead box P3-positive regulatory T cells (FOXP3 Tregs). Finally, weekly administration of IL-2-containing hydrogel partially prevented autoimmune diabetes while injections of soluble IL-2 did not. Hydrogel delivery may reduce the number of injections required in IL-2 treatment protocols for autoimmune diabetes. Graphical abstract

Observations on intelligence and behavior in 15 patients with Legius syndrome

Legius syndrome is a RAS-MAPK syndrome characterized by pigmentary findings similar to neurofibromatosis type 1 (NF1), but without tumor complications. Learning difficulties and behavioral problems have been reported to be associated with Legius syndrome, but have not been studied systematically. We investigated intelligence and behavior in 15 patients with Legius syndrome and 7 unaffected family members. We report a mean full-scale IQ of 101.57 in patients with Legius syndrome, which does not differ from the control group. We find a significantly lower Performance IQ in children with Legius syndrome compared to their unaffected family members. Few behavioral problems are present as assessed by the Child Behavior Checklist (CBCL) questionnaire. Our observations suggest that, akin to the milder somatic phenotype, the cognitive phenotype in Legius syndrome is less severe than that of NF1. © 2011 Wiley-Liss, Inc.status: publishe

Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes

Defining the genetic contribution of rare variants to common diseases is a major basic and clinical science challenge that could offer new insights into disease etiology and provide potential for directed gene- and pathway-based prevention and treatment. Common and rare nonsynonymous variants in the GCKR gene are associated with alterations in metabolic traits, most notably serum triglyceride levels. GCKR encodes glucokinase regulatory protein (GKRP), a predominantly nuclear protein that inhibits hepatic glucokinase (GCK) and plays a critical role in glucose homeostasis. The mode of action of rare GCKR variants remains unexplored. We identified 19 nonsynonymous GCKR variants among 800 individuals from the ClinSeq medical sequencing project. Excluding the previously described common missense variant p.Pro446Leu, all variants were rare in the cohort. Accordingly, we functionally characterized all variants to evaluate their potential phenotypic effects. Defects were observed for the majority of the rare variants after assessment of cellular localization, ability to interact with GCK, and kinetic activity of the encoded proteins. Comparing the individuals with functional rare variants to those without such variants showed associations with lipid phenotypes. Our findings suggest that, while nonsynonymous GCKR variants, excluding p.Pro446Leu, are rare in individuals of mixed European descent, the majority do affect protein function. In sum, this study utilizes computational, cell biological, and biochemical methods to present a model for interpreting the clinical significance of rare genetic variants in common disease

Significance of association of SNVs with CALM count by simple linear regression adjusting for age and sex using self-reported European-American samples.

<p>Note:</p><p>a) unt: untransformed CALM count; log: log-transformed CALM count; add: additive effect of minor allele; dom: dominant effect of minor allele.</p><p>b) *: p-value≤0.05, **: p-value≤0.01.</p><p>Significance of association of SNVs with CALM count by simple linear regression adjusting for age and sex using self-reported European-American samples.</p

Significance of association of SNPs with CALM count by tiled regression of the discovery set.

<p>Note:</p><p>a) additive effect of minor allele,</p><p>b) *: p-value≤0.05.</p><p>Significance of association of SNPs with CALM count by tiled regression of the discovery set.</p