Genetic and environmental factors influencing the risk and course of eating disorders

Eating disorders are debilitating conditions characterized by dysregulated eating and/or weight-control behaviors leading to significant impairment of psychosocial functioning and/or physical health. Both environmental factors and variation in multiple genetic variants of small to moderate effect influence eating disorder etiology and maintenance. This thesis aims to expand knowledge in both areas, first by studying how/whether individuals with a pre-existing eating disorder are affected by the COVID-19 pandemic (Studies I & II). And second, by performing the first genome-wide association study (GWAS) of binge-eating behavior, complemented with a larger GWAS of anorexia nervosa (AN) and the first GWAS of AN subtypes (Study III).

Individuals with an eating disorder may be uniquely affected by an unprecedented global event such as the COVID-19 pandemic. Study I showed that during April-May 2020, individuals in the United States and the Netherlands (n = 1,021) with a pre-existing eating disorder reported increased levels of eating disorder symptomatology due to the pandemic, as well as increased self-reported levels of anxiety. A lack of social support, increased time spent in a triggering environment, and a lack of structure were commonly reported as factors that may worsen eating disorder course. Furthermore, those in treatment mostly shifted to online care. Last, a substantial portion also experienced positive changes, which indicates that the pandemic may have differential impact depending on everyone’s unique circumstances.

We extended these findings in Study II where we assessed eating disorder symptomatology, well-being, and care access in the first year (April 2020 – June 2021) of the COVID-19 pandemic among individuals with a current or past eating disorder in the Netherlands, United States, and Sweden. Among those with a self-reported current eating disorder (n = 776), 10-38% still reported to engage more frequently in eating disorder symptoms due to the pandemic, one year into the pandemic. In the United States and the Netherlands, this was less than at the start of the pandemic; in Sweden, the proportion remained relatively low at both time points. Furthermore, anxiety levels were moderate in all countries, but higher in the United States during the early phase of the pandemic. This pattern was observed to a lesser extent in the Netherlands; and in Sweden, anxiety levels remained stable over time. The majority self-reported increased levels of anxiety and depression due to the COVID-19 pandemic, also one year after the start of the pandemic.

In Study III, we performed GWAS of binge-eating behavior, AN, and AN subtypes. Study III revealed five genome-wide significant loci for binge-eating behavior (broadly defined); nine loci for AN (of which six replicated and three novel); one genome-wide significant locus for the AN restricting subtype, and none for the AN binge-eating/purging type. Genetic correlation analyses indicate that, on a genetic level, binge-eating behavior (like AN) overlaps with a range of psychiatric and body composition-related traits. We also observed notable differences in genetic correlation analyses between AN and binge eating: divergent relationships with body composition-related traits; differential associations with several psychiatric traits; and only AN was statistically significantly associated with certain metabolic traits. Furthermore, none of the genome-wide significant loci between AN and binge-eating behavior overlap. Last, we also refine our understanding of AN by performing two subtype GWAS, which suggest that the restricting subtype of AN overlaps more strongly with body-composition traits than the bingeeating/ purging subtype of AN.

In conclusion, this thesis shows that individuals with a pre-existing eating disorder generally experienced symptom worsening during the early phase of the pandemic (April- May 2020), and that a substantial portion was still negatively affected one year into the pandemic (April-June 2021). Furthermore, this thesis identified the first genome-wide significant loci for the transdiagnostic symptom binge-eating behavior. Findings imply that binge-eating behavior can confidently be considered a psychiatric phenotype with genetic associations linked to body composition, anchoring it within the eating disorderspectrum. While binge-eating behavior partly shows similarities with AN on a genetic level, it also has distinct features. Together with the AN subtype GWAS findings, results indicate that genes involved in anthropometric traits are relevant for eating disorders but that the direction of effect may diverge depending on the eating disorder type. Altogether, this thesis highlights the importance of studying the contribution of both environmental and genetic factors in eating disorder risk and course.

List of scientific papers

I. Termorshuizen JD, Watson HJ, Thornton LM, Borg S, Flatt RE, MacDermod CM, Harper LE, van Furth EF, Peat CM, Bulik CM. Early impact of COVID-19 on individuals with self-reported eating disorders: A survey of ~1,000 individuals in the United States and the Netherlands. Int J Eat Disord. 2020 Nov;53(11):1780-1790. Epub 2020 Jul 28.
https://doi.org/10.1002/eat.23353

II. Termorshuizen JD, Sun Q, Borg S, Mantilla EF, Goode RW, Peat CM, Thornton LM, Watson H, van Furth EF, Birgegård A, Bulik CM. Longer-term impact of COVID-19 among individuals with self-reported eating disorders in the United States, the Netherlands, and Sweden. Int J Eat Disord. 2023 Jan;56(1):80-90. Epub 2022 Oct 13.
https://doi.org/10.1002/eat.23824

III. Termorshuizen JD, Davies H, Lee SH, Johnson J, Munn-Chernoff MA, Thornton LM, Zvrskovec Källberg J, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Huckins LM, Bulik CM, Breen G, Coleman JRI. Genome-wide association studies of binge-eating behavior and anorexia nervosa yield insights into unique and shared biology of eating disorder phenotypes. [Manuscript]