Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed which included 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at onset, early-onset AN (< 13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (SNP-h2) were 0.01-0.04 for age at onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age at onset and early-onset AN estimated from independent GWASs significantly predicted age at onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions Our results provide evidence consistent with a common variant genetic basis for age at onset and implicate biological pathways regulating menarche and reproduction.Peer reviewe

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Associations between Attention-Deficit/Hyperactivity Disorder and various eating disorders: A Swedish nationwide population study using multiple genetically informative approaches

Background Although attention-deficit hyperactivity/impulsivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs (OED, including bulimia nervosa [BN]). Methods We applied different genetically informative designs to register-based information of a Swedish nationwide population (N=3,550,118). We first examined the familial co-aggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores (PRS) and ED symptoms, and between AN PRS and ADHD symptoms, in a genotyped population-based sample (N=13,472). Results Increased risk of all types of EDs was found in individuals with ADHD (any ED: OR [95% CI]=3.97 [3.81-4.14], AN: 2.68 [2.15-2.86], OED: 4.66 [4.47-4.87], BN: 5.01 [4.63-5.41]) and their relatives compared to individuals without ADHD and their relatives. The magnitude of the associations reduced as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with OED (0.37 [0.31-0.42]) than with AN (0.14 [0.05-0.22]). ADHD PRS correlated positively with ED symptom measures overall and sub-scales “drive for thinness” and “body dissatisfaction”, despite small effect sizes. Conclusions We observed stronger genetic association with ADHD for non-AN EDs than AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders

Médicos y farmacéuticos como artistas de las bellas artes, pinturas y escultura

Entre las muchas profesiones, las profesiones de salud -a saber, los profesionales médicos y farmacéuticos, académicos e investigadores- parecen tener una posición única: por un lado, están cerca a las ciencias naturales; por otro lado, sirven el cuerpo y la mente de su prójimo. Idealmente, este servicio es dado principalmente no con el propósito de satisfacción propia, sino más bien con el interés de ayudar a la humanidad.Entre las muchas profesiones, las profesiones de salud -a saber, los profesionales médicos y farmacéuticos, académicos e investigadores- parecen tener una posición única: por un lado, están cerca a las ciencias naturales; por otro lado, sirven el cuerpo y la mente de su prójimo. Idealmente, este servicio es dado principalmente no con el propósito de satisfacción propia, sino más bien con el interés de ayudar a la humanidad

Alterations of drug disposition in high altitude

Exposure of the human body to high altitude (H) results in significant physiologic changes and may precipitate mountain sickness, ranging from mild symptoms above 2500 m to severe symptoms above 4000 m, and coma a teven higher altitude. In a previous study in our labs we found et vivo an increase in meperidine (M) upteke wilh increase in number of erythrocytes (RBG). One of the major physiologic changes at H is a increase in hematocrit and RBC. The study was carried out in three groups of healthy volunteers (18-2' y): at sea level (L), at 4360 m the day after arrival at H (HA), and at 4360 m in subjects residing &gt; 10 mo at H (HC), 0.75 mglkg of M was administered I.M. between 8-9 a.m. Blood was collected for 12 h. M was measured in whole blood (WB), plasma (P) and plasma -water (PW). The pharmacokinetic parameters derived from curve-fitting were analyzed by ANOVA. Significant changes were found in P and (WB) for λz ↓ L vs HA (L vs HA), L vs HC; CL/F ↓ L vs HA (L vs HA), L vs HC, and MRT ↑ L vs HA (L vs HA), L vs HC. The hematocrit significantly increased L vs HA, L vs HC end HA vs HC from 43.3 to 46.4 to 53.4%. The RBC binding significantly increase from 42.3% at L to 43.8% at HA to 50.9% at GC. The extent 01 protein binding shows a trend to decrease with H, however, it is not significant. Free M concentration in PW measured after 1,2, and 4 h was significently increased after 2 and 4 h.Exposure of the human body to high altitude (H) results in significant physiologic changes and may precipitate mountain sickness, ranging from mild symptoms above 2500 m to severe symptoms above 4000 m, and coma a teven higher altitude. In a previous study in our labs we found et vivo an increase in meperidine (M) upteke wilh increase in number of erythrocytes (RBG). One of the major physiologic changes at H is a increase in hematocrit and RBC. The study was carried out in three groups of healthy volunteers (18-2' y): at sea level (L), at 4360 m the day after arrival at H (HA), and at 4360 m in subjects residing &gt; 10 mo at H (HC), 0.75 mglkg of M was administered I.M. between 8-9 a.m. Blood was collected for 12 h. M was measured in whole blood (WB), plasma (P) and plasma -water (PW). The pharmacokinetic parameters derived from curve-fitting were analyzed by ANOVA. Significant changes were found in P and (WB) for λz ↓ L vs HA (L vs HA), L vs HC; CL/F ↓ L vs HA (L vs HA), L vs HC, and MRT ↑ L vs HA (L vs HA), L vs HC. The hematocrit significantly increased L vs HA, L vs HC end HA vs HC from 43.3 to 46.4 to 53.4%. The RBC binding significantly increase from 42.3% at L to 43.8% at HA to 50.9% at GC. The extent 01 protein binding shows a trend to decrease with H, however, it is not significant. Free M concentration in PW measured after 1,2, and 4 h was significently increased after 2 and 4 h

Physiologically based novel peroral modified release drug delivery system: Self-destructing hydrogel piston-pump

Peroral modified drug delivery systems on the market release fue drug by either 0-order, 1º-order, square root oftime or mixed rate. This means that the drugis released mto the gastrointestinallumenin amounts being either constantper unit of time or decreasingwith time. However, physiologically absorption from the GI lumen gets slower and more difficult past the small intestme. A novel drug delivery system is described far 24 horus drug delivery which follows approximate 0-orden release throughout the small intestine, but releases increasing amounts of drug once in the colon ta compensate for increasingly more difficult absorption. Nearly constant steady state drug plasma concentrations are achieved . The novel drug delivery system is a two layered dosage form with an immediate release layer and a modified release layer. The latter ene is a hydrogel piston pump comprised of a drug core layer and a hydrogel swelling layer, embedded into a semipermeable shell by compression coating. The upper site of the shell has a release channel in the center.Peroral modified drug delivery systems on the market release fue drug by either 0-order, 1º-order, square root oftime or mixed rate. This means that the drugis released mto the gastrointestinallumenin amounts being either constantper unit of time or decreasingwith time. However, physiologically absorption from the GI lumen gets slower and more difficult past the small intestme. A novel drug delivery system is described far 24 horus drug delivery which follows approximate 0-orden release throughout the small intestine, but releases increasing amounts of drug once in the colon ta compensate for increasingly more difficult absorption. Nearly constant steady state drug plasma concentrations are achieved . The novel drug delivery system is a two layered dosage form with an immediate release layer and a modified release layer. The latter ene is a hydrogel piston pump comprised of a drug core layer and a hydrogel swelling layer, embedded into a semipermeable shell by compression coating. The upper site of the shell has a release channel in the center