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

Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained

Study of the genetic structure of the Colombian amerind population

IP 1115-05-132-9

Genetic selection for natural disease resistance against brucellosis and foot and mouth disease virus in colombian criollo cattle

IP 2121-12-134-94resistencia natural a las infecciones virales / Albeiro Lopez,Ana E. Arango, Jorge E. Ossa. -- En: Revista;colombiana de ciencias pecuarias. -- Vol. 13, no. 1 (2000); p.37-45. -- ISSN 01200690 -- Caracterizacion de;recursos geneticos autoctonos en Colombia / Olivera AngelM. ...[et al.]'-- en: Revista escuela nacional de;policia general Santander seccional Rafael Reyes. -- No. 3(dic.2001); p.39-40. -- ISSN 0124549X--;Resistencia natural del ganado blanco ojinegro (Bon) a lainfeccion por virus de estomatitis vesicular (Vev) y;rinotraqueitis infecciosa bovina (RIB) / Restrepo S. ... [et al.] -- En: susceptibilidad a los subtipos A24-C;y O1-C de la fiebre aftosa y la capacidad de produccion deIFN,por parte1 (2000); p. 37-45. -- ISSN 01200690;'-- caracterizacion de Recursos geneticos autoctonos en COLombia/ Olivera(BON) / Albeiro Lopez, Ana E.;Arango, Fabio N. Zuluaga, Jose Barrera, Jorge E. Ossa. --En:Iatreia. --Vol. 13, no. 2 (jun. 2000); p.;53-120. -- ISSN 01210793. -- Genotipicacion de la resistencianatural delganado blanco ojinegro (BON) a la;salmonella dublin / Omar A. Saldarriaga, Maria T. Rugeles,JaimeI. Velasquez, Gabriel Bedoya, Gary Adams,;Jorge E. Ossa. -- En: Iatreia. -- vol. 13, no. 2 (jun. 2000);p.53-120. -- ISSN 01210793. -- Caracterizacion;'-- en: Proceedings of the Global Conference On Conservation ofDomestic Animal Genetic Resources (4 : 1998;Aug. 17-21 : Colombia) -- [s.l. : s.n.], 1998 -- p. ; 28 cm. --Ifn mediated restriction of fmdv in bovine;fibroblast / A. Lopez ... [et al.] -- En: International symposium on positive strand RNA visure cm. --;ARTICULO(S) EN REVISTA: Receptores celulares, interferon yapoptosis en laresistencia natural a las;infecciones virales / Albeiro Lopez, Ana E. Arango, JorgeE. Ossa. -- En:Revista colombiana de ciencias;pecuarias. -- Vol. 13 (2000); p. 37-45. -- ISSN 01200690 -'- Biologia molecular y epizootiologia del virus de;la fiebre aftosa / Albeiro Lopez, Ana E. Arango, Jorge E.Ossa.'-- en: Revista colombiana de ciencias;PONENCIAS EN CONGRESO(S): Toward the recovery of criollo cattlein Colombia / M. Olivera Angel. ... [et al.];pecuarias. -- Vol. 13 (2000); p. 37-45. -- ISSN 01200690 -'- Ganado blancoorejinegro (BON): una alternativa;genotipica y fenotipica de la resistencia natural del ganado blanco oreginegro (BON) a la salmonella dublin /;O. A. Saldarriaga, M. T. Rugeles, J. I. Velasquez, G. Bedoya,J.E. Ossa.'-- en: Revista colombiana Ciencias;pecuarias. -- Vol. 12 (sep. 1999); p. 51-52. -- ISSN 01200690--Analisisde resistencia/susceptibilidad al;virus de la fiebre aftosa en el ganado blanco orejinegro (BON)/A. Lopez,... [et al.] -- En: Revista;colombiana ciencias pecuarias. -- Vol. 12 (sep. 1999); p.51-52.-- ISSN 01200690 -- Estructura molecular y;poblacional del ganado criollo Colombiano (GCC) / GabrielBedoya... [et al.] -- En: Revista colombiana;ciencias pecuarias. -- vol. 14, no. 2 (2001); p. 107-125.'-- ISSN 01200690-- Receptores celulares, interferon;y apoptosis en la resistencia natural a las infecciones virales/ AlbeiroLopez, Ana E. Arango, Jorge Ossa. --;para la produccion en Colombia / Albeiro Lopez ... [et al.] --En: Revistacolombiana de ciencias pecuarias.; Vol. 13 (2000 ); p. 37-45. -- ISSN 01200690 -- Receptores celulares, interferon y apoptosis en la;En: Revista colombiana ciencias pecuarias. -- vol. 13, no.1 (2000); p. 14-18. -- ISSN 0120069

Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures

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

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