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

Acceptability of Multiparticulate Dosing Using Sympfiny® Delivery System with Children (Age 1–12)

This study investigated multiparticulate formulation administered over a two-week period of time via the Sympfiny® system with children of ages 1–12 years. The study was conducted with parent–child pairs (N = 120 total participants) following a specific dose strategy to mimic PURIXAN’s dosing guidelines based upon the child’s age. PURIXAN® (mercaptopurine) and Methotrexate have been identified as potential chemotherapy drugs that could benefit from reformulation into multiparticulate. Multiparticulate drugs have advantages as they can be flavorless, and do not require liquid reconstitution and do not require refrigeration. The study included three parts: initial in-person session, 14 days of at-home use, and a final in-person session. The in-person sessions were conducted at HS Design’s (HSD) (Morristown, NJ, USA) offices located in Morristown, New Jersey, where a study moderator captured and recorded all subjective comments by participants and observed device use to identify use errors. The participants were instructed to administer a dose (placebo) for the next 14 days and at each dose delivery to fill out a daily survey regarding their experience. Overall, the cumulative survey responses and feedback collected during the in-person sessions suggest that child participants ages 5–12 years old found multiparticulate to be an acceptable formulation and would be willing to take this medication if they were sick. Over time, more children ages 1–4 did not open their mouths; consistently around 15–20% of 1–4 years olds spat the placebo. However, approximately 95% of parents found the Sympfiny® system acceptable and indicated that they would use it to deliver medication to their child

K–8 Classroom Self-Collection Using XpressCollect Nasal Swab: A Usability and Efficacy Study

This study demonstrates that students in kindergarten through eighth grade can use the XpressCollect nasal swab to self-collect a specimen under the guidance of a teacher. This phased study was conducted with parents, teachers, and students. Phases 1 and 2 were conducted as interviews with teachers and parents to assess the suitability of the XpressCollect for children in kindergarten through eighth grade. Additionally, teacher and parent feedback was obtained to develop and optimize the instructional materials for subsequent phases. In Phases 3 and 4, teachers guided small groups and full classes of students through the sample collection process with XpressCollect. The samples collected by the students were sent to a laboratory to analyze the effectiveness of specimen self-collection based on the presence of ribonuclease P (RNase P) on each nasal swab. The presence of RNase P enables disease determination; thus, student samples were analyzed for adequate or inadequate sampling. All students in kindergarten through eighth grade are capable of self-collecting an anterior nares specimen with XpressCollect, as the laboratory results identified acceptable RNase P Ct values for the samples collected in a classroom setting

Analysis of Shared Heritability in Common Disorders of the Brain

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology