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

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Colorectal cancer adjuvant chemotherapy trends among a nonelderly veteran cohort at a southern veterans health administration

Abstract Background For patients with high‐risk stage II or stage III colorectal cancer (CRC), adjuvant chemotherapy (AC) improves survival, yet use varies substantially across medical oncology settings. Aim Utilization of guideline concordant CRC AC was assessed at a Veterans Health Administration (VHA) facility to determine quality improvement initiatives. Methods and Results The study was a retrospective review of CRC surgeries from January 1, 2000 to December 31, 2015 at a South Regional VHA. Inclusion criteria consisted of pathologic high‐risk stage II or stage III CRC, with exclusion for age ≥80, age ≥75 hospitalized with major co‐morbidity in the prior year, and death or discharge to hospice within 30 days of the index surgery. The primary predictor was year‐group; partitioned 2000–2005, 2006–2010, 2011–2015 to account for changes in NCCN high risk stage II definitions. Primary outcome was AC receipt. Secondary outcome was reason for chemotherapy omission. Among 180 eligible surgeries (121 colon and 59 rectal cancers), patients were mostly male (96%), white (79%) and with median age 64 years. Overall, 117 (65%) received AC. Compared to 2000–2005, patients undergoing surgery between 2011 and 2015 were less likely to receive AC (odds ratio 0.35; 95% confidence interval [CI] 0.14–0.82), due to more patients declining AC (27% vs. 6%, p < .01) in the NCCN eligible cohort (N = 180), and (32% vs. 8%, p < .01) in an analysis of patients who completed appointments and had AC recommended by providers (N = 146). Conclusions Survival benefitting AC decreased over time among a nonelderly Veteran cohort eligible for AC. Evaluating care decisions and trends within other VHA facilities and outside the VHA are warranted

Feasibility evaluation of the Reaching Out to Kids with Emotional Trauma (ROcKET) intervention in an elementary school: a single-arm, single-centre, feasibility study based on the RE-AIM framework

Objective The study purpose was to describe feasibility of implementation of the Reaching Out to Kids with Emotional Trauma (ROcKET) intervention. We hypothesised that the ROcKET Intervention would be feasible in a poor resource school.Design We performed a single-arm, single-centr feasibility study of an intervention pilot, based on the RE-AIM framework.Setting The intervention was delivered in a single K-4th elementary charter school in the Nashville, TN area, in a low-resource community.Participants 57 elementary school children attending our partner school and reporting exposure to at least one adverse childhood experience (ACE) and their parents.Interventions The Reaching Out to Kids with Emotional Trauma (ROcKET) intervention is a school-based multilevel intervention (individual child, family and school) that promotes positive health behaviours in children who have been exposed to ACEs.Outcomes Outcomes were gathered qualitatively via focus groups. The primary outcome was feasibility. The secondary outcomes were implementation outcomes according to the RE-AIM framework, including Reach, Effectiveness, Adoption and Implementation.Results Of 105 eligible children, 57 children and their parents participated (54%) with 31 (54%) girls, 47 (82%) Black/African American, 5 (9%) Hispanic and 5 (9%) white. The school staff implemented all planned ROcKET sessions with &gt;90% fidelity in each session, and 52 (91%) of children who completed the final intervention session went on to complete 6 month follow-up assessments. The average attendance at the in-school child sessions was 57 students (87%), and 35 (61%) of parents attended at least one family session, with 25 (44%) of parents attending at least half of the family sessions. 13 (23%) parents participated in the focus groups. Qualitative data suggested high parent participant satisfaction, uptake of positive health behaviours targeted by the intervention and increased quality of life.Conclusions Our study suggests that the ROcKET intervention was feasible and acceptably delivered in a local elementary school with high reach to low-income and minority populations. These data suggest that schools, especially those serving low-income and minority children, can be an appropriate avenue for interventions designed to address health disparities. Data from this study will be used to advise a pilot study of the intervention

Associations between Verbal Learning Slope and Neuroimaging Markers across the Cognitive Aging Spectrum

A symptom of mild cognitive impairment (MCI) and Alzheimer's disease (AD) is a flat learning profile. Learning slope calculation methods vary, and the optimal method for capturing neuroanatomical changes associated with MCI and early AD pathology is unclear. This study cross-sectionally compared four different learning slope measures from the Rey Auditory Verbal Learning Test (simple slope, regression-based slope, two-slope method, peak slope) to structural neuroimaging markers of early AD neurodegeneration (hippocampal volume, cortical thickness in parahippocampal gyrus, precuneus, and lateral prefrontal cortex) across the cognitive aging spectrum [normal control (NC); (n=198; age=76±5), MCI (n=370; age=75±7), and AD (n=171; age=76±7)] in ADNI. Within diagnostic group, general linear models related slope methods individually to neuroimaging variables, adjusting for age, sex, education, and APOE4 status. Among MCI, better learning performance on simple slope, regression-based slope, and late slope (Trial 2-5) from the two-slope method related to larger parahippocampal thickness (all p-values&lt;.01) and hippocampal volume (p&lt;.01). Better regression-based slope (p&lt;.01) and late slope (p&lt;.01) were related to larger ventrolateral prefrontal cortex in MCI. No significant associations emerged between any slope and neuroimaging variables for NC (p-values ≥.05) or AD (p-values ≥.02). Better learning performances related to larger medial temporal lobe (i.e., hippocampal volume, parahippocampal gyrus thickness) and ventrolateral prefrontal cortex in MCI only. Regression-based and late slope were most highly correlated with neuroimaging markers and explained more variance above and beyond other common memory indices, such as total learning. Simple slope may offer an acceptable alternative given its ease of calculation

The dose of behavioral interventions to prevent and treat childhood obesity: a systematic review and meta-regression

Abstract Background A better understanding of the optimal “dose” of behavioral interventions to affect change in weight-related outcomes is a critical topic for childhood obesity intervention research. The objective of this review was to quantify the relationship between dose and outcome in behavioral trials targeting childhood obesity to guide future intervention development. Methods A systematic review and meta-regression included randomized controlled trials published between 1990 and June 2017 that tested a behavioral intervention for obesity among children 2–18 years old. Searches were conducted among PubMed (Web-based), Cumulative Index to Nursing and Allied Health Literature (EBSCO platform), PsycINFO (Ovid platform) and EMBASE (Ovid Platform). Two coders independently reviewed and abstracted each included study. Dose was extracted as intended intervention duration, number of sessions, and length of sessions. Standardized effect sizes were calculated from change in weight-related outcome (e.g., BMI-Z score). Results Of the 258 studies identified, 133 had sufficient data to be included in the meta-regression. Average intended total contact (# sessions x length of sessions) was 27.7 (SD 32.2) hours and average duration was 26.0 (SD 23.4) weeks. When controlling for study covariates, a random-effects meta-regression revealed no significant association between contact hours, intended duration or their interaction and effect size. Conclusions This systematic review identified wide variation in the dose of behavioral interventions to prevent and treat pediatric obesity, but was unable to detect a clear relationship between dose and weight-related outcomes. There is insufficient evidence to provide quantitative guidance for future intervention development. One limitation of this review was the ability to uniformly quantify dose due to a wide range of reporting strategies. Future trials should report dose intended, delivered, and received to facilitate quantitative evaluation of optimal dose. Trial registrations The protocol was registered on PROSPERO (Registration # CRD42016036124 )