Manifestations of genetic risk and intergenerational transmission of risk for eating disorders (MoBa-Eat)

Methodological refinement ahead of finalising core outputs & completed analyses investigating intergenerational transmissionThe over-arching aim of MoBa-Eat is to advance our understanding of the development of eating disorders in the general population and within families. In 2022, MoBa-Eat researchers have refined methodologies that will be deployed to achieve this aim in the remaining years of the project, while contributing to several relevant external projects.Preliminary results relating to the first aim of the MoBa-Eat project - identifying the phenotypic manifestations of genetic risk for eating disorders in males and females at different stages of development - were reported last year. Recognition of the need to increase the analytic sample size in order to robustly detect small associations between genetic risk for eating disorders and early life behaviours in both boys and girls led to the MoBa-Eat team re-doubling efforts to support the completion of the quality-control of the full sample of genotyped individuals in the MoBa sample. This was achieved in spring of this year, and MoBa-Eat researchers contributions resulted in co-authorship of a preprint describing the process and resultant data. MoBa-Eat aim 1 analyses using these data have been re-run and the results are currently being written up for submission to a journal in 2023. The second aim of the MoBa-Eat project involves understanding the intergenerational transmission of risk for eating disorders. Last year, we reported on the plans to address this aim and the resulting analytic project - entitled "Parental body mass index (BMI) and offspring childhood body size and eating behaviour: causal inference via parental comparisons and extended children of twins structural equation modelling" - has now been completed, and will shortly be uploaded to a preprint server and submitted for publication. In it, we found that higher parental BMI was linked to offspring eating behaviours, but that the fact parents and their children share some of the same genetic risk factors was a better explanation of this link than any causal process involving parental behaviour. In addition to this work, methodological refinement has again been a focus of the team in respect of the second aim in 2022. MoBa-Eat researchers have been a key part of a paper published in the journal Molecular Psychiatry (see publications list) using a novel method designed to separate the effects of different members of a family on the behaviours - in this case, those related to attention-deficit hyperactivity disorder - exhibited by children. Application of this method to measures of eating behaviours in the MoBa sample will help to shed further light on the mechanisms by which risk for eating disorders is transmitted within families during the remainder of the project. The third aim of the MoBa-Eat project involves assessing whether or not early life environmental factors interact with genetic propensities to increase risk for developing eating disorders. In 2022, MoBa-Eat researchers have been actively developing models suitable for achieving this aim. One such model is introduced in a preprint (uploaded to the medRxiv preprint server - see publications list - and currently under-going peer review for formal publication), in which the associations between maternal at-risk drinking and child emotional and behavioural problems are first adjusted for confounding by factors that differ between families, and then assessed depending on genetic vulnerabilities to stressful environments among children. Application of this approach to associations between a range of early-life environmental factors and measures of eating behaviours among children is planned for 2023, and will help in fulfilling the remaining aim of MoBa-Eat.

MoBa-Eat team working to disentangle genetic and environmental sources of parent-offspring similarity in eating behavioursThis project is part of the Psychiatric Genetic Epidemiology (PaGE) group at Nic Waals Institute of Lovisenberg Diaconal Hospital, led by Alexandra Havdahl. It started in July 2019 with the recruitment of postdoctoral fellow Ziada Ayorech, and continues into 2022 with research fellow Laurie Hannigan working in collaboration with Dr Ayorech.The results of primary analyses addressing the project's first research question: "How does genetic risk for eating disorders manifest in females and males at different stages of development?" are now available in pre-print form (https://psyarxiv.com/w57h9). The MoBa-Eat team is in the process of updating these analyses using newly available genetic data from a larger sub-sample of the MoBa cohort, allowing findings to be reported with increased precision and certainty. This is especially important given the nature of the effects we have uncovered, which are generally very small. The updated results will be preprinted and submitted for peer review and formal publication during the next reporting period. Based on the need, identified during the first analytic project, to be better able to distinguish small effects from random variation, MoBa-Eat researchers have been developing a new framework to carry out these kinds of analyses, and will submit this for publication during 2022. The secondary aim of the MoBa-Eat project was to leverage the family structure of the MoBa sample to disentangle genetic and environmental modes of risk transmission from parents to offspring. To address this aim, the MoBa-Eat team have been working on an analytic project entitled "Parental body mass index and offspring birth weight, body mass index and eating behaviour: genetic analyses in the Norwegian Mother, Father and Child Cohort". The specific aims of this project are to investigate associations between maternal BMI and offspring weight and BMI (measured from birth until the latest time point in childhood at which sufficient data are available), as well as with offspring eating behaviour traits (e.g. emotional over- and under-eating, satiety responsiveness and binge eating disorder). The project will then compare the magnitude of such associations to that of paternal BMI with the same outcomes. Finally, pedigree-based statistical models will be used to partition the overlap between parental BMI and offspring outcomes into components explained by genetic transmission, extended family environment, and residual covariance. These analyses are due to be completed and written up for submission during the next reporting period. To help understand the broader context in which eating disorders exist, MoBa-Eat researchers are investigating "social patterning" in eating disorders, in a cross-cultural study using data sources from the UK (the Avon Longitudinal Study of Parents and Children), Denmark (the Danish National Birth Cohort), and MoBa. In this project, we compare the magnitude and direction of associations between socioeconomic position and eating disorders as measured by self-report versus registry-based diagnosis, and explore international differences in these patterns. Results from these analyses will be written up during the next reporting period. This year, MoBa-Eat researchers also contributed to a major international collaborative publication on the influence on common genetic variation on the age of onset of anorexia nervosa. In addition, 2021 saw the presentation of results at the IEA World Congress of Epidemiology of work involving several MoBa-Eat team members among its authors, examining the causal effect of BMI on neurodevelopment using a novel within-family research design. The MoBa-Eat fellow has also contributed as co-author to several papers on psychiatric genetics over the past year (see publication list).

The development of eating disorders: Early manifestations of genetic risk and intergenerational transmission of riskEating disorders (ED) are common psychiatric conditions associated with disability, impaired life quality, chronicity, and a high mortality rate. We capitalise on recent advances in genetic methods to investigate the early manifestations of genetic risk to ED and the transmission of ED risk from one generation to the next.This postdoctoral project is conducted as part of the Psychiatric Genetic Epidemiology (PaGE) group at Nic Waals Institute of Lovisenberg Diaconal Hospital, led by Alexandra Havdahl. The fellowship started in July 2019 with the recruitment of postdoctoral fellow Ziada Ayorech who has a PhD in behavioral genetics from King’s College London and expertise in genetic analyses of complex traits. We have completed analyses addressing the project's first research question: How does genetic risk for eating disorders manifest in females and males at different stages of development. First, a genetic score that indicates the number of anorexia nervosa risk variants that a person carries, was calculated for over 15 000 Norwegian children participating in the Norwegian, Mother, Father and Child Cohort Study (MoBa). This genetic score was then systematically related to broad behavioural domains capturing growth, eating problems, neurodevelopmental and internalising problems, disruptive behaviour and personality traits, measured from birth to 8 years. The findings will offer an important contribution to the literature demonstrating whether genetic risk for eating disorders is manifested in observational traits in early childhood, which has important implications for these under-detected and under-diagnosed conditions. The paper is in submission. Analyses have also been carried out to address the project's second research aim: Investigate causality in associations between early life exposures and child symptoms of eating disorders. Here the postdoctoral researcher seeks to combine epidemiological methods of causal inference with genetic data in order to test whether metabolic, inflammatory and psychiatric exposures are causally related to childhood symptoms of disordered eating. This second research aim capitalises on new genomic evidence supporting a reconceptualisation of anorexia nervosa as a metabo-psychiatric disorder. The causal inference results will be an integral first step in addressing the urgent need for findings that contribute to more effective detection, prevention and treatment of eating disorders. The paper is in preparation for submission. Analyses are ongoing for multiple additional papers addressing the fellowship aims. Ziada Ayorech has contributed to publishing several other research articles as part of PaGE in 2020, which are listed under research papers (preprint articles are specified). She has also presented the project plans and outputs at conferences and seminars, including oral presentation at the 2020 World Congress of Psychiatric Genetics (WCPG) and an invited talk at the Psychiatric Genomics Consortium Eating Disorders Working Group meeting in Oct 2020. She presented on the methodology of calculating polygenic scores to social scientists as invited talk for the Oslo Meeting for Genetics & Social Sciences in Jan 2020. During the first year of the fellowship, Ziada Ayorech was supported by the PaGE group in applying for international funding. The fellow has received a prestigious Horizon 2020 Marie Skłodowska-Curie actions (MSCA) Individual Fellowship from the European Research Council (supervisors: Eivind Ystrøm at the University of Oslo and Alexandra Havdahl from the PaGE group at Lovisenberg).

The development of eating disorders: Early manifestations of genetic risk and intergenerational transmission of riskEating disorders (ED) are common psychiatric conditions associated with disability, impaired life quality, chronicity, and a high mortality rate. We capitalise on recent advances in genetic methods to investigate the early manifestations of genetic risk to ED and the transmission of ED risk from one generation to the nextThe project started in July 2019 by hiring a postdoctoral researcher with expertise in genetic analyses of complex traits. Within the first 6 months, the postdoctoral researcher has completed analyses addressing the project's first research question: How does genetic risk for eating disorders manifest in females and males at different stages of development. First, a genetic score that indicates the number of anorexia nervosa risk variants that a person carries, was calculated for over 15 000 Norwegian children participating in the Norwegian, Mother, Father and Child Cohort Study (MoBa). This genetic score was then systematically related to broad behavioural domains capturing growth, eating problems, neurodevelopmental and internalising problems, disruptive behaviour and personality traits, measured from birth to 8 years. The findings will offer an important contribution to the literature demonstrating that genetic risk for eating disorders is expressed in behaviourally modifiable traits in early childhood, which has important implications for these under-detected and under-diagnosed conditions. The first draft of the research paper has been written and will be revised and submitted for publication this year. Since the project start date, the postdoctoral researcher has also begun to design analyses addressing the project's second research aim: Investigate causality in associations between early life exposures and child symptoms of eating disorders. Here the postdoctoral researcher seeks to combine epidemiological methods of causal inference with genetic data in order to test whether metabolic, inflammatory and psychiatric exposures are causally related to childhood symptoms of disordered eating. This second research aim capitalises on new genomic evidence supporting a reconceptualisation of anorexia nervosa as a metabo-psychiatric disorder. The causal inference results will be an integral first step in addressing the urgent need for findings that contribute to more effective detection, prevention and treatment of eating disorders. To facilitate analyses on the project's second aim, the postdoctoral researcher has now completed an advanced causal inference training course, led by experts in Mendelian Randomization, a method which uses genetic variation to examine the causal effect of modifiable exposures on health-related outcomes. Importantly, the postdoctoral researcher has begun the project with a one-year research exchange at the University of Bristol, which has provided valuable access to experts in genetic epidemiology with extensive experience in translating empirical results into clinical and public health impact.