A longitudinal, epigenome-wide study of DNA methylation in anorexia nervosa: results in actively ill, partially weight-restored, long-term remitted and non-eating-disordered women

Abstract

Background:This study explored state-related tendencies in DNA methylation in people with anorexia nervosa. Methods: We measured genome-wide DNA methylation in 75 women with active anorexia nervosa (active), 31 women showing stable remission of anorexia nervosa (remitted) and 41 women with no eating disorder (NED). We also obtained postintervention methylation data from 52 of the women from the active group. Results: Comparisons between members of the active and NED groups showed 58 differentially methylated sites (Q < 0.01) that corresponded to genes relevant to metabolic and nutritional status (lipid and glucose metabolism), psychiatric status (serotonin receptor activity) and immune function. Methylation levels in members of the remitted group differed from those in the active group on 265 probes that also involved sites associated with genes for serotonin and insulin activity, glucose metabolism and immunity. Intriguingly, the direction of methylation effects in remitted participants tended to be opposite to those seen in active participants. The chronicity of Illness correlated (usually inversely, at Q < 0.01) with methylation levels at 64 sites that mapped onto genes regu lating glutamate and serotonin activity, insulin function and epigenetic age. In contrast, body mass index increases coincided (at Q < 0.05) with generally increased methylation-level changes at 73 probes associated with lipid and glucose metabolism, immune and inflammatory processes, and olfaction. Limitations: Sample sizes were modest for this type of inquiry, and findings may have been subject to uncontrolled effects of medication and substance use. Conclusion: Findings point to the possibility of reversible epigenetic alterations in anorexia nervosa, and suggest that an adequate pathophysiological model would likely need to include psychiatric, metabolic and immune components.

Behavioral Alterations in Mice Carrying Homozygous HDAC4A778T Missense Mutation Associated With Eating Disorder

“…While the family in which ESRRA R188Q mutation was found has a high rate of AN and comorbidity of obsessive-compulsive disorder (OCD), another family in which HDAC4 A786T mutation was found has higher rates of BN but significantly lower rates of comorbid OCD. Multiple independent studies have shown that many CpG sites located in genomic region around 5 upstream of HDAC4 gene are differentially methylated in the peripheral tissues of patients with AN (Booij et al, 2015;Kesselmeier et al, 2018;Subramanian et al, 2018;Sild and Booij, 2019;Steiger et al, 2019), further supporting the role of HDAC4 in the pathophysiology of EDs. In the followup mouse studies, we found that Esrra knockout mice display behavioral deficits relevant to EDs, including reduced food intake, decreased motivation to work for high-fat diet (HFD), and social subordination (Cui et al, 2015).…”

Applying epigenetic science to the understanding of eating disorders: a promising paradigm for research and practice

“…Although the studies in question are heterogenous with respect to methodology and results [ 18 ▪ , 23 ], available findings point to the potentials of epigenetic processes to constitute molecular mechanisms that could link environmental impacts, experienced at various moments throughout the life cycle (perinatal, childhood and adult) to mental-health outcomes, including eating disorders [ 8 , 18 ▪ , 23 ]. Importantly, methylation of some genes can also be altered by psychotherapeutic, nutritional or pharmacologic interventions [ 25 , 26 ▪▪ ], which raises the promise that changes in DNA methylation could serve as a marker for disease risk, staging, prognosis or therapeutic response.…”

“…To date, three studies have conducted epigenome-wide analyses in individuals with eating disorders [ 26 ▪▪ , 30 , 31 ], all three involving anorexia nervosa. The most recent of these [ 26 ▪▪ ] compared epigenome-wide DNA methylation patterns in leukocytes of 75 individuals with anorexia nervosa, 31 in remission from anorexia nervosa for at least 1 year, and 41 normal-weight healthy eaters [ 26 ▪▪ ]. It also assessed DNA methylation after 4 months of standardized treatment for anorexia nervosa.…”

“…Finally, body mass index increases after 4 months of treatment correlated with methylation changes in genes linked to lipid and glucose metabolism and immune function. Notably, DNA methylation patterns from individuals remitted for 1 year did not differ from those seen in normal eaters, suggesting the possibility that illness-induced methylation changes might be reversed by nutritional rehabilitation [ 26 ▪▪ ]. As an additional note, we find it intriguing that epigenome-wide analyses conducted by our group [ 26 ▪▪ , 30 ] and by an independent group [ 31 ] corroborate associations between anorexia nervosa, on the one hand, and altered methylation in NR1H3 (involved in lipid metabolism and inflammation) and TNXB (associated with connective-tissue disorders), on the other.…”

Anorexia Nervosa

“…Research on candidate genes examined the serotonergic system (5-HT system), dopaminergic system, and opioidergic system that affect appetite, reward mechanism, mood, and weight; nevertheless, statistically significant results have not been presented so far [51]. Genome wide studies showed a relation between chromosomes 1, 11, and 12 and genes related to leptin regulation, lipid and glucose metabolism, serotonin receptor activities, and the immune system [52][53][54][55]. This genetic presentation is also consistent with the clinical presentation of anorexia.…”