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

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.[Background] As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited.[Objective] The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.[Methods] We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.[Results] We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.[Conclusions] Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.This project was funded by The Michael J. Fox Foundation (ID 15015.02)Peer reviewe

Tomographic Parameters for the Detection of Keratoconus: Suggestions for Screening and Treatment Parameters

Tomographic corneal evaluation has added significantly more information in the evaluation of the ectatic cornea. Additional information from the posterior cornea and a full corneal thickness map in addition to anterior corneal analysis has increased the ability to identify early and subtle corneal changes. Although these newer examination modalities have increased our sensitivity in refractive screening, problems still persist when attempting to assure treatment trials (such as collagen cross-linking) for early disease are performed to an appropriate patient population. This article will review past and present diagnostic capabilities with a particular emphasis on refractive screening and early treatment studies and stress the limitations of our current diagnostic ability when it comes to diagnosing early ectatic change.Univ Arizona, Dept Ophthalmol & Vis Sci, Tucson, AZ USAUniversidade Federal de São Paulo, São Paulo & Rio de Janeiro Corneal Tomog & Biomec, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, São Paulo & Rio de Janeiro Corneal Tomog & Biomec, Rio de Janeiro, BrazilWeb of Scienc

Reliability analysis of successive Corvis ST® measurements in keratoconus 2 years after accelerated corneal crosslinking compared to untreated keratoconus corneas

Purpose To assess the reliability of successive Corvis ST® measurements (CST, Oculus, Wetzlar, Germany) in keratoconus (KC)≥2 years after accelerated corneal crosslinking (9 mW/cm2 , 10 min, 5.4 J/cm2 ) compared to untreated KC corneas. Methods Three successive CST measurements per eye were performed in≥2 years after CXL (CXLG, n=20 corneas of 16 patients) and a control group consisting of non-operated, ABC-stage-matched KC corneas according to Belin’s ABCD KC grading (controls, n=20 corneas, 20 patients). Main outcome measures included maximal keratometry (Kmax), the Belin/ Ambrósio-Enhanced-Ectasia-Deviation-Index BAD-D; the biomechanical parameters A1 velocity, deformation amplitude (DA) ratio 2 mm, Ambrósio relational thickness to the horizontal profle (ARTh), integrated radius, stifness parameter A1 (SP-A1), and the Corvis Biomechanical Factor (CBiF, the linearized term of the Corvis Biomechanical Index). Mean values, standard deviations, and Cronbach’s alpha (CA) were calculated. Results Both groups were tomographically comparable (BAD: 11.5±4.7|11.2±3.6, p=0.682, Kmax: 60.5±7.2|60.7±7.7, p=0.868 for controls|CXLG, paired t-test). A1 velocity (mean±SD: 0.176±0.02|0.183±0.02, p=0.090, CA: 0.960|0.960), DA ratio 2 mm (6.04±1.13|6.14±1.03, p=0.490, CA: 0.967|0.967), integrated radius (12.08±2.5|12.42±1.9, p=0.450, CA: 0.976|0.976), and CBiF (4.62±0.6|4.62±0.4, p=0.830, CA: 0.965|0.965) were also comparable (controls|CXLG). ARTh was signifcantly higher in controls (177.1±59, CA: 0.993) than after CXL (155.21±65, p=0.0062, CA: 0.993) and SP-A1 was signifcantly higher after CXL (59.2±13, CA: 0.912) than in controls (52.2±16, p=0.0018, CA: 0.912). Conclusion ARTh and SP-A1 difered signifcantly between controls and CXLG. Biomechanical measurements were generally of excellent reliability in both groups. CXL seems to afect biomechanical measurements of human corneas over more than 2 years

Visual Acuity Outcomes of the Boston Keratoprosthesis Type 1: Multicenter Study Results

To report logarithm of the minimal angle of resolution (logMAR) visual outcomes of the Boston keratoprosthesis type 1. Prospective cohort study. Preoperative, intraoperative, and postoperative parameters of 300 eyes of 300 patients who underwent implantation of a Boston keratoprosthesis type 1 device between January 2003 and July 2008 by 1 of 19 surgeons at 18 medical centers were collected. After an average of 17.1 ± 14.8 months, visual acuity improved significantly (P < .0001) to a mean final value of 0.89 ± 0.64 (20/150). There were also significantly fewer eyes with light perception (6.7%; n = 19; P < .0001), although 3.1% (n = 9) progressed to no light perception. There was no association between age (P = .08), sex (P = .959), operative side (P = .167), or failure (P = .494) and final visual acuity. The median time to achieve 20/200 visual acuity was 1 month (95% confidence interval 1.0-6.0) and it was retained for an average of 47.8 months. Multivariate analysis, controlling for preoperative visual acuity, demonstrated 2 factors associated with final visual outcome: chemical injury was associated with better final vision (P = .007), whereas age-related macular degeneration was associated with poorer vision (P < .0001). The Boston keratoprosthesis type 1 is an effective device for rehabilitation in advanced ocular surface disease, resulting in a significant improvement in visual acuity. Eyes achieved a mean value of 20/150 (0.89 ± 0.64 logMAR units) after 6 months and this was relatively stable thereafter. The best visual prognosis is observed in chemical injury eyes, whereas the worst prognosis is in aniridia, although the latter has limited visual potential

Comprehensive anterior segment normal values generated by rotating Scheimpflug tomography

PURPOSE: To identify normal values for tomographic parameters that are considered useful in screening patients for refractive surgery.SETTING: Private center, Albany, New York, USA.DESIGN: Database study.METHODS: A Pentacam HR Scheimpflug system was used to examine 1 randomly selected eye of patients to determine normal values of 21 parameters considered the most clinically applicable for surgical screening. Normality of data was evaluated using the Kolmogorov-Smirnov test. Statistical analyses were performed using the Student t test to compare means and the 2-paired sample Wilcoxon signed-rank test. Results are displayed in 95.0% and 97.5% confidence intervals (CIs).RESULTS: the study evaluated 341 adults. High-end outliers at the 97.5% CI were 46.1 diopters (D) for flat keratometry (K), 47.4 D for steep K, 3.4 D for astigmatism, 3.8 mu m for anterior chamber depth, 4 mu m for front apical elevation, 5 mu m for front elevation at the thinnest point, and 12 mu m for front elevation in the central 4.0 mm. Respective posterior elevation values were 7 mu m, 13 mu m, and 25 mu m, with a progression index maximum of 1.53 and mean of 1.19, difference between apical and thinnest pachymetric reading of 7 mu m, a maximum K of 48.2 D, and an inferior superior ratio of 1.44 D. Low-end outliers were a maximum Ambrosio relational thickness of 335 and a mean of 425, minimum pachymetry of 479 mu m, thickness at the apex of 481 mu m, and central 4.0 mm corneal volume of 6.31 mm(3).CONCLUSION: Scheimpflug-derived corneal tomography identified key refractive surgery parameters that may be useful in screening refractive surgical patients. (C) 2013 ASCRS and ESCRSUniv Arizona, Coll Med, Tucson, AZ USAUniv Arizona, Dept Ophthalmol & Vis Sci, Tucson, AZ USASouthern Arizona Vet Adm Healthcare Syst, Tucson, AZ USAAlbany TLC Laser Eye Ctr, Albany, NY USAUniversidade Federal de São Paulo, Dept Ophthalmol, São Paulo, BrazilRio de Janeiro Corneal Tomog & Biomech Study Grp, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Dept Ophthalmol, São Paulo, BrazilWeb of Scienc