The Eating Disorders Genetics Initiative (EDGI): study protocol

Bulik, Cynthia M.; Thornton, Laura M.; Parker, Richard; Kennedy, Hannah; Baker, Jessica H.; MacDermod, Casey M.; Guintivano, Jerry; Cleland, Lana; Miller, Allison L.; Harper, Lauren; Larsen, Janne Tidselbak; Yılmaz, Zeynep; Grove, Jakob; Sullivan, Patrick F.; Petersen, Liselotte; Jordan, Jennifer; Kennedy, Martin A.; Martin, Nicholas G.

doi:10.1186/s12888-021-03212-3

Cited by 26 publications

(23 citation statements)

References 46 publications

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“…It is possible that AN is a multifactorial disease. Recent genomic association studies provide evidence of a genetic predisposition for a body weight set point in AN [6][7][8][9]. In this framework, AN could be not only a psychiatric disorder but also a metabolic one [10].…”

Section: Introductionmentioning

confidence: 99%

Anti-hypothalamus autoantibodies in anorexia nervosa: a possible new mechanism in neuro-physiological derangement?

et al. 2022

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Purpose Anorexia nervosa (AN) is a serious and complex mental disorder affecting mainly young adult women. AN patients are characterized by low body weight in combination with self-induced starvation, intense fear of gaining weight, and distortion of body image. AN is a multifactorial disease, linked by recent evidence to a dysregulation of the immune system. Methods In this pilot study, 22 blood serums from AN patients were tested for the presence of autoantibodies against primate hypothalamic periventricular neurons by immunofluorescence and by a home-made ELISA assay. Cellular fluorescence suggests the presence of autoantibodies which are able to recognize these neurons (both to body cell and fiber levels). By means of ELISA, these autoantibodies are quantitatively evaluated. In addition, orexigenic and anorexigenic molecules were measured by ELISA. As control, 18 blood serums from healthy age matched woman were analysed. Results All AN patients showed a reactivity against hypothalamic neurons both by immunofluorescence and ELISA. In addition, ghrelin, pro-opiomelanocortin (POMC), and agouti-related peptide (AGRP) were significantly higher than in control serums (p < 0.0001). In contrast, leptin was significantly lower in AN patients than controls (p < 0.0001). Conclusions Immunoreaction and ELISA assays on AN blood serum suggest the presence of autoantibodies AN related. However, it is not easy to determine the action of these antibodies in vivo: they could interact with specific ligands expressed by hypothalamic cells preventing their physiological role, however, it is also possible that they could induce an aspecific stimulation in the target cells leading to an increased secretion of anorexigenic molecules. Further studies are needed to fully understand the involvement of the immune system in AN pathogenesis. Level of evidence V, descriptive study.

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Section: Introductionmentioning

confidence: 99%

Anti-hypothalamus autoantibodies in anorexia nervosa: a possible new mechanism in neuro-physiological derangement?

et al. 2022

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“…Recruiting a suitably large sample for an ARFID GWAS is realistically achievable if a collaborative, multinational approach is taken. The Psychiatric Genomics Consortium (PGC) has been instrumental in coordinating study populations large enough to perform highly powered GWAS in many psychiatric disorders including ADHD [ 94 ], ASD [ 95 ], bipolar disorder [ 96 ], major depression [ 97 ], schizophrenia [ 56 ], Alzheimer’s disease [ 98 ], OCD [ 99 ], Tourette syndrome [ 100 ], post-traumatic stress disorder (PTSD) [ 101 ], substance use disorders [ 102 ], and EDs [ 103 , 104 ]. The Eating Disorders Working Group of the PGC has expanded to include ARFID, and identification of existing samples and collection of new samples is beginning.…”

Section: Discussionmentioning

confidence: 99%

“…A blueprint of how to achieve a large-scale, multinational GWAS cohort has already been provided in the PGC-led Eating Disorder Genetics Initiative (EDGI) [ 104 ]. EDGI utilises a standardised set of phenotypic assessments provided as an online survey, with DNA sampling via an at-home saliva sampling kit mailed directly to the participant.…”

Section: Discussionmentioning

confidence: 99%

How genetic analysis may contribute to the understanding of avoidant/restrictive food intake disorder (ARFID)

et al. 2022

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Avoidant/restrictive food intake disorder (ARFID) was introduced in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Unlike anorexia nervosa, ARFID is characterised by avoidant or restricted food intake that is not driven by weight or body shape-related concerns. As with other eating disorders, it is expected that ARFID will have a significant genetic risk component; however, sufficiently large-scale genetic investigations are yet to be performed in this group of patients. This narrative review considers the current literature on the diagnosis, presentation, and course of ARFID, including evidence for different presentations, and identifies fundamental questions about how ARFID might fit into the fluid landscape of other eating and mental disorders. In the absence of large ARFID GWAS, we consider genetic research on related conditions to point to possible features or mechanisms relevant to future ARFID investigations, and discuss the theoretical and clinical implications an ARFID GWAS. An argument for a collaborative approach to recruit ARFID participants for genome-wide association study is presented, as understanding the underlying genomic architecture of ARFID will be a key step in clarifying the biological mechanisms involved, and the development of interventions and treatments for this serious, and often debilitating disorder.

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“…Outcomes could be improved with increasing understanding of pathogenic mechanisms responsible for the development of AN (Kaye & Bulik, 2021). GWAS have been reported and larger studies are underway to expand upon the GWAS findings and deepen understandings of the heritability of eating disorders more broadly, including bulimia nervosa and binge‐eating disorder (Bulik et al, 2021). Accumulating evidence indicates that SSVs have diverse functional effects on genotypic variability (Fotsing et al, 2019; Pytte, Anderton, et al, 2020; Pytte, Flynn, et al, 2020; Theunissen et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Bridging the gap: Short structural variants in the genetics of anorexia nervosa

Berthold

Pytte

Bulik

et al. 2022

Intl J Eating Disorders

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Anorexia nervosa (AN) is a devastating disorder with evidence of underexplored heritability. Twin and family studies estimate heritability (h2) to be 57%–64%, and genome‐wide association studies (GWAS) reveal significant genetic correlations with psychiatric and anthropometric traits and a total of nine genome‐wide significant loci. Whether significantly associated single nucleotide polymorphisms identified by GWAS are causal or tag true causal variants, remains to be elucidated. We propose a novel method for bridging this knowledge gap by fine‐mapping short structural variants (SSVs) in and around GWAS‐identified loci. SSV fine‐mapping of loci associated with complex disorders such as schizophrenia, amyotrophic lateral sclerosis, and Alzheimer's disease has uncovered genetic risk markers, phenotypic variability between patients, new pathological mechanisms, and potential therapeutic targets. We analyze previous investigations' methods and propose utilizing an evaluation algorithm to prioritize 10 SSVs for each of the top two AN GWAS‐identified loci followed by Sanger sequencing and fragment analysis via capillary electrophoresis to characterize these SSVs for case/control association studies. Success of previous SSV analyses in complex disorders and effective utilization of similar methodologies supports our proposed method. Furthermore, the structural and spatial properties of the 10 SSVs identified for each of the top two AN GWAS‐associated loci, cell adhesion molecule 1 (CADM1) and NCK interacting protein with SH3 domain (NCKIPSD), are similar to previous studies. We propose SSV fine‐mapping of AN‐associated loci will identify causal genetic architecture. Deepening understandings of AN may lead to novel therapeutic targets and subsequently increase quality‐of‐life for individuals living with the illness. Public Significance Statement Anorexia nervosa is a severe and complex illness, arising from a combination of environmental and genetic factors. Recent studies estimate the contribution of genetic variability; however, the specific DNA sequences and how they contribute remain unknown. We present a novel approach, arguing that the genetic variant class, short structural variants, could answer this knowledge gap and allow development of biologically targeted therapeutics, improving quality‐of‐life and patient outcomes for affected individuals.

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The Eating Disorders Genetics Initiative (EDGI): study protocol

Cited by 26 publications

References 46 publications

Anti-hypothalamus autoantibodies in anorexia nervosa: a possible new mechanism in neuro-physiological derangement?

Anti-hypothalamus autoantibodies in anorexia nervosa: a possible new mechanism in neuro-physiological derangement?

How genetic analysis may contribute to the understanding of avoidant/restrictive food intake disorder (ARFID)

Bridging the gap: Short structural variants in the genetics of anorexia nervosa

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