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

The Anorexia Nervosa Genetics Initiative (ANGI): overview and methods

This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/ which permits use, distribution and reproduction in any medium, provided the original work is properly cited. This author accepted manuscript is made available following 12 month embargo from date of publication (October 2018) in accordance with the publisher’s archiving policyBackground Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research. Methods ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H. Results Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable. Conclusions Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection.Please refer to published article

Predicting ADHD by Assessment of Rutter’s Indicators of Adversity in Infancy

Background: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with early onset. ADHD is associated with significant morbidity and mortality, partly due to delayed diagnosis. Identification of children at high risk for developing ADHD could lead to earlier diagnosis and potentially change the negative trajectory of the illness for the better. Since early psychosocial adversity is considered to be a likely etiological risk factor for ADHD, markers of this construct may be useful for early identification of children at high risk. Therefore, we sought to investigate whether Rutter’s indicators of adversity (low social class, severe marital discord, large family size, paternal criminality, maternal mental disorder, and placement in out-of-home care) assessed in infancy could serve as early predictors for the development of ADHD. Methods and Findings: Using data from the Danish nationwide population-based registers, we established a cohort consisting of all 994,407 children born in Denmark between January 1st 1993 and December 31st 2011 and extracted dichotomous values for the six Rutter’s indicators of adversity at age 0–12 months (infancy) for each cohort member. The cohort members were followed from their second birthday and the association between the sum of Rutter’s indicators of adversity (RIA-score) in infancy and subsequent development of ADHD was estimated by means of Cox regression. Also, the number needed to screen (NNS) to detect one case of ADHD based on the RIA-scores in infancy was calculated. During follow-up (9.6 million person-years), 15,857 males and 5,663 females from the cohort developed ADHD. For both males and females, there was a marked dose-response relationship between RIA-scores assessed in infancy and the risk for developing ADHD. The hazard ratios for ADHD were 11.0 (95%CI: 8.2–14.7) and 11.4 (95%CI: 7.1–18.3) respectively, for males and females with RIA-scores of 5–6, compared to males and females with RIA-scores of 0. Among males with RIA-scores of 5–6, 37.6% (95%CI: 27.0–50.7) had been diagnosed with ADHD prior to the age of 20, corresponding to a NNS of 3.0 (95%CI: 2.2–4.0). Conclusions: Rutter’s indicators of adversity assessed in infancy strongly predicted ADHD. This knowledge may be important for early identification of ADHD