Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes

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

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

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

First published: 16 February 202

Monocular amblyopia and higher order aberrations

This study compared the corneal and total higher order aberrations between the fellow eyes in monocular amblyopia. Nineteen amblyopic subjects (8 refractive and 11 strabismic) (mean age 30 ± 11 years) were recruited. A range of biometric and optical measurements were collected from the amblyopic and non-amblyopic eye including; axial length, corneal topography and total higher order aberrations. For a sub-group of eleven non-presbyopic subjects (6 refractive and 5 strabismic amblyopes, mean age 29 ± 10 years) total higher order aberrations were also measured during accommodation (2.5 D stimuli). Amblyopic eyes were significantly shorter and more hyperopic compared to non-amblyopic eyes and the interocular difference in axial length correlated with both the magnitude of anisometropia and amblyopia (both p < 0.01). Significant differences in higher order aberrations were observed between fellow eyes, which varied with the type of amblyopia. Refractive amblyopes displayed higher levels of 4th order corneal aberrations C(4, 0)(spherical aberration), C(4, 2)(secondary astigmatism 90°) and C(4, −2)(secondary astigmatism along 45°) in the amblyopic eye compared to the non-amblyopic eye. Strabismic amblyopes exhibited significantly higher levels of C(3, 3)(trefoil) in the amblyopic eye for both corneal and total higher order aberrations. During accommodation, the amblyopic eye displayed a significantly greater lag of accommodation compared to the non-amblyopic eye, while the changes in higher order aberrations were similar in magnitude between fellow eyes. Asymmetric visual experience during development appears to be associated with asymmetries in higher order aberrations, in some cases proportional to the magnitude of anisometropia and dependent upon the amblyogenic factor

Accommodation "error" and retinal image quality

Aim: A modified wavefront sensor was used to investigate the\ud effect of accommodative errors on retinal image quality.\ud Methods: Ten subjects were presented with six vergence stimuli\ud between 0.17 D and 5.00 D. For each vergence distance, subjective\ud visual acuity and ocular wavefronts were measured. Wavefronts\ud were analysed for natural pupil sizes and for a fixed threemillimetre\ud pupil diameter. Visual Strehl ratios computed in the\ud frequency domain (VSOTF) and retinal images were calculated\ud for each condition.\ud Results: Subjective visual acuity was significantly improved at\ud intermediate vergence distances (1.00 D and 2.00 D; p < 0.01),\ud and decreased significantly at 5.00 D compared with 0.17 D\ud (p < 0.05). VSOTF magnitude was associated with subjective visual\ud acuity and VSOTF peak location correlated with accommodation\ud error. Apparent accommodative errors due to spherical aberration\ud were highly correlated with accommodative lead and lag for natural\ud pupils (R2 = 0.80) and accounted for 93 per cent of the total\ud accommodative error.\ud Conclusions: The combination of higher-order aberrations and\ud accommodative errors improved retinal image quality compared\ud with accommodative errors or higher order aberrations alone.\ud The one to one stimulus/response slope should not be considered\ud as ideal in the presence of higher-order aberrations. Pupil size and\ud higher order aberrations play an important role in ASR

Corneal optics after reading, microscopy and computer work

Purpose: To compare lid-induced changes in corneal optics following reading, microscopy and computer work. \ud Methods: Nine subjects with normal ocular health were recruited for the study. Five subjects were myopic, two were emmetropic, one was astigmatic and one was hyperopic. Corneal topography was measured before and after 60 mins of reading a novel, performing a blood cell counting task on a microscope and Internet searching. Corneal topography data were used to derive the corneal wavefront Zernike coefficients up to the fourth order. A meridian analysis of instantaneous corneal power along the upper 90-degree semi-meridian was performed to examine local changes caused by eyelid pressure. Digital photography was used to capture body posture and eyelid position during the tasks. \ud Results: Each of the three tasks showed systematically different effects on both the characteristics and location of corneal topography changes. Reading and microscopy generally exhibited larger and more centrally located changes compared with the computer task. Differences in wavefront aberration characteristics between the three tasks were apparent in both lower and higher order aberrations. The location of corneal distortions differed significantly between microscopy and computer work, with microscopy causing distortions to occur closer to the videokeratoscope measurement axis compared with computer work (p = 0.015). \ud Conclusions: Reading, microscopy and computer work have different effects on corneal aberrations. The results are in agreement with the hypothesis that lidinduced corneal aberrations may play a role in myopia development