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

El espacio provincial en la península ibérica

En el origen de este monográfico se halla la voluntad de unos historiadores de la Antigüedad de cuestionar la validez del mapa, propuesto por E. Albertini en 1923, de la trama provincial que siguió a la reforma de Diocleciano en Hispania. Para trazarlo, E. Albertini utilizó el «principio de acomodación» que habría permitido la preservación de las estructuras territoriales romanas, en las de la Iglesia en la Alta Edad Media. Para abordar esta cuestión, se hizo necesario el diálogo con historiadores medievales. Este diálogo que abarca los siglos entre el iv y el xii ha tenido el mérito de superar la cuestión inicial para adoptar el enfoque epistemológico más fértil del «spatial turn» en el que las provincias ya no se pueden considerar únicamente como meros territorios congelados, sino como espacios marcados por la discontinuidad y la plasticidad de su uso. À l’origine de cette monographie se trouve le souci de certains historiens de l’Antiquité de contester la validité de la carte de la trame provinciale, proposée par E. Albertini en 1923, qui a fait suite à la réforme de Dioclétien en Hispanie. Pour dessiner cette carte, E. Albertini a utilisé le « principe de l’accommodement » qui aurait permis le maintien des structures territoriales romaines dans celles de l’Église au début du Moyen Âge. Pour aborder cette question, un dialogue avec les historiens médiévaux était nécessaire. Ce dialogue, qui s’étend sur plusieurs siècles, entre le ive et le xiie, a eu le mérite de dépasser la question initiale pour adopter l’approche épistémologique plus féconde du « spacial turn » dans lequel les provinces ne peuvent plus être considérées comme de simples territoires figés, mais comme des espaces marqués par la discontinuité et la plasticité de leur utilisation. At the origin of this monograph lies the concern of some historians of antiquity to challenge the validity of the map of the provincial grid, proposed by E. Albertini in 1923, which followed the reform of Diocletian in Hispania. To draw this map, E. Albertini used the "principle of accommodation" that would have allowed the Roman territorial structures to be maintained in those of the Church in the early Middle Ages. To address this question, a dialogue with medieval historians was necessary. This dialogue, which extends over several centuries, between the 4th and the 12th century, has had the merit of going beyond the initial question to adopt the more fertile epistemological approach of the "spatial turn" in which the provinces can no longer be considered as mere frozen territories, but as spaces marked by the discontinuity and plasticity of their use

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