What next for eating disorder genetics? Replacing myths with facts to sharpen our understanding

Abstract

Substantial progress has been made in the understanding of anorexia nervosa (AN) and eating disorder (ED) genetics through the efforts of large-scale collaborative consortia, yielding the first genome-wide significant loci, AN-associated genes, and insights into metabo-psychiatric underpinnings of the disorders. However, the translatability, generalizability, and reach of these insights are hampered by an overly narrow focus in our research. In particular, stereotypes, myths, assumptions and misconceptions have resulted in incomplete or incorrect understandings of ED presentations and trajectories, and exclusion of certain patient groups from our studies. In this review, we aim to counteract these historical imbalances. Taking as our starting point the Academy for Eating Disorders (AED) Truth #5 “Eating disorders affect people of all genders, ages, races, ethnicities, body shapes and weights, sexual orientations, and socioeconomic statuses”, we discuss what we do and do not know about the genetic underpinnings of EDs among people in each of these groups, and suggest strategies to design more inclusive studies. In the second half of our review, we outline broad strategic goals whereby ED researchers can expand the diversity, insights, and clinical translatability of their studies.

The Role of Circadian Rhythms and Sleep in Anorexia Nervosa

“…As the anorexia nervosa GWAS focused on broadly defined anorexia nervosa based on billing codes and/or self-report, we were unable to interrogate anorexia nervosa subtypes, such as restrictive, binge-eating/purging, or atypical anorexia nervosa . Our analyses only considered participants of European ancestry, as the genetic discoveries were from predominantly European cohorts and the transferability of variants into non-European populations remains unknown . It is worth noting that anorexia nervosa prevalence remains currently highest among European and Western cultures, is rapidly rising among young adolescent girls, and is likely underdiagnosed in men and individuals from minoritized racial and ethnic groups, necessitating future large investigations on early or late onset anorexia nervosa and anorexia in non-European populations.…”

“…22 Our analyses only considered participants of European ancestry, as the genetic discoveries were from predominantly European cohorts and the transferability of variants into non-European populations remains unknown. 52 It is worth noting that anorexia nervosa prevalence remains currently highest among European and Western cultures, is rapidly rising among young adolescent girls, 53 and is likely underdiagnosed in men and individuals from minoritized racial and ethnic groups, 52 necessitating future large investigations on early or late onset anorexia nervosa 54 and anorexia in non-European populations. We presented MR P values unadjusted for multiple testing because our study is exploratory in nature.…”

Thoughtful Phenotype Definitions Empower Participants and Power Studies

“…In these instances, even perfectly followed or applied diagnostic guidelines will result in imperfect diagnoses, since symptoms listed rely on stereotypes rather than disease pathology. For example, the inclusion of amenorrhoea in anorexia nervosa diagnostic guidelines biases diagnosis towards people who menstruate -away from children, cis men, and post-menopausal women, all of whom are nevertheless at risk of developing eating disorders [15][16][17]. Similarly, ADHD symptoms may be rated more highly among boys, leading to under-diagnosis in girls [18].…”

“…Similarly, ADHD symptoms may be rated more highly among boys, leading to under-diagnosis in girls [18]. These biases may be internal as well as external, preventing affected individuals from seeking diagnoses because they do not see themselves reflected in a stereotyped description of a disorder [15].…”

“…Towards this goal, the use of case/control definitions are likely unhelpful at best and damaging at worst. Dismissing symptoms because they do not fit a specific diagnosis is likely to alienate patients; this will be especially dangerous if symptoms are dismissed because they do not yet meet sufficient criteria for severity (for example, dismissing individuals with insufficiently low BMI in eating disorder clinics [15]). Further, the use of overly clinical or old-fashioned language may alienate patients or may prevent young people from identifying with or engaging in appropriate and helpful interventions or research studies.…”