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

Ann and David Skillrud

Ann (Stroink) and David Skillrud share their reasons for choosing IWU. They are both members of the class of 1976, Biology and Chemistry majors, respectively, and SIU Medical students at the time of the interview. Ann transferred in as a second semester Freshman from a large school and cites her interest in being taught by PhDs as one reason. She enjoyed being challenged in her science classes and also enjoyed classes in the Humanities and Art History and enjoyed taking Voice lessons in the School of Music. David also chose IWU for the benefit of learning from PhDs, some who also served as Department Chairs, and all of whom were accessible for meetings when he needed them. He was a tennis player and appreciated that, while academics came first, faculty made allowances when he needed to adjust his schedule. Both commented on how well prepared they were for medical school and that IWU faculty prepared recommendations that were respected by the admissions panel at SIU

Temperature increase exacerbates apoptotic neuronal death in chemically-induced ischemia.

It is well-established that hyperthermia increases neuronal death and worsens stroke outcome. However, little is known about the mechanisms of how hyperthermia is involved in this neuronal death process. In the present study, we examined how temperature increase exacerbates neuronal death using a model of chemical ischemia. Chemical ischemia was induced by treating SH-SY5Y neuroblastoma cells with sodium azide and deoxyglucose. Temperature increase was treated by placing the cells at 37°C (control) and 41°C (experimental). Cell survival was determined by trypan blue assay and ATP levels were measured with ATP assay kits. Protein expression was detected by western blot. Treatment with sodium azide resulted in cell death in a dose-responsive manner. Increased temperature worsened the ATP depletion and cell volume shrinkage. Temperature increase also enhanced ER stress as demonstrated by the elevated level of phospho-eIF2α and C/EBP homologous protein (CHOP). Inhibition of CHOP expression significantly decreased sodium azide-induced neuronal death. In addition, the increased temperature intensified the activation of caspase-3, an apoptotic effector protease, and inhibition of capspase-3 significantly reduced cell death. These findings support that temperature increase worsened the neuronal death by depleting intracellular ATP, inducing ER stress response and activating apoptotic signal transduction

Apoptosis was detected with Annexin V-FITC and PI staining.

<p>Cells were double stained with Annexin V-FITC and PI after the treatments for 1 hour. Apoptosis with Annexin V-FITC positive staining (green fluorescence) was detected in cells treated with high temperature alone, sodium azide/2-DG alone or the combination of sodium azide/2-DG plus high temperature. Representative images were shown in the figure. w/: with; w/o: without.</p

Temperature increase worsened sodium azide/2-DG induced reduction of cellular volume.

<p>Cells received different treatments for 1 hour, and then cell volume was measured by BD FACScan flow cytometer with an aid of Cell Quest Pro. The data were acquired using FCS with voltage E00. A total of 50,000 cells were analyzed per sample. Flow cytometry analysis showed smaller forward scatter value following the treatment with sodium azide/2-DG or increased temperature alone. Combination treatment of sodium azide/2-DG and increased temperature produced addictive actions in the decrease of forward scatter value. Data were representative of one of three independent experiments. w/: with; w/o: without.</p

Caspase-3 was activated following the treatments.

<p>Cells were subjected to treatments with sodium azide/2-DG, increased temperature or combination of sodium azide/2-DG plus increased temperature for a period of 30 minute or 1 hour. Control cells received no treatment. Cleavage of caspase-3 and PARP-1 were analyzed with western blot. β-actin was used as a loading control.</p

Temperature increase worsened sodium azide/2-DG induced ER stress.

<p>(A) Cells were subjected to treatments with sodium azide/2-DG, increased temperature or combination of sodium azide/2-DG plus increased temperature for a period of 30 minute or 1 hour. Control cells received no treatment. The cells were then collected and protein expressions were analyzed with western blot. β-actin was used as a loading control. (B) CHOP shRNA transfection significantly inhibited CHOP expression. SH-SY5Y cells were transfected with lentiviral particles encoding copGFP (mock) or CHOP shRNA. CHOP protein levels were analyzed by western blot. β-actin was used as a loading control. (C) CHOP shRNA transfection significantly reduced sodium azide/2-DG-induced cell death. Mock or CHOP shRNA transfected SH-SY5Y cells were treated with sodium azide/2-DG for 1 hour at 37°C and 41°C. Cell death was detected with trypan blue exclusion assay. * (p<0.05) and † (p<0.01) denote significant difference from the group received mock transfection.</p

Intracellular and extracellular ATP levels changed following treatments.

<p>Neuronal death was induced by treating the cells with 0.5 mM 2-DG and 5 mM sodium azide for the indicated time. Control cells were incubated with fresh regular medium for 10 minutes. (A) Intracellular ATP was measured. Error bars represent mean ± SEM. n = 4. * denotes significant difference from 37°C controls (<i>p</i><0.01); † denotes significant difference from 41°C control (<i>p</i><0.01); ‡ denotes significant difference from the cells received the treatment at 37°C (<i>p</i><0.05). (B) Extracellular ATP was measured in the culture medium following the treatments. Error bars represent mean ± SEM. n = 4. *denotes significant difference from 37°C controls (<i>p</i><0.01); † denotes significant difference from the group received the treatment with sodium azide/2-DG at 37°C (<i>p</i><0.01).</p