Genome-wide Association Study Identifies Eight Risk Loci and Implicates Metabo-psychiatric Origins for Anorexia Nervosa

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%. Mortality rates are higher than those in other psychiatric disorders, and outcomes are unacceptably poor. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

Citing Articles

From Clinic to Mechanisms: Multi-Omics Provide New Insights into Cerebrospinal Fluid Metabolites and the Spectrum of Psychiatric Disorders.

Wen J, Li Y, Chen Y, Li Y, Yu B, Liu H Mol Neurobiol. 2025; .

PMID: 40085352 DOI: 10.1007/s12035-025-04773-0.

Application of Genetic Testing for Anorexia Nervosa: An Ethical Analysis.

Ramsay S, Allison K, Temples H, Sarasua S, Boccuto L Brain Behav. 2025; 15(3):e70406.

PMID: 40059471 PMC: 11891269. DOI: 10.1002/brb3.70406.

Mendelian randomization analyses uncover causal relationships between brain structural connectome and risk of psychiatric disorders.

Xiao K, Chang X, Ye C, Zhang Z, Ma T, Su J medRxiv. 2025; .

PMID: 40034754 PMC: 11875323. DOI: 10.1101/2025.02.20.25322606.

Mapping the regulatory effects of common and rare non-coding variants across cellular and developmental contexts in the brain and heart.

Marderstein A, Kundu S, Padhi E, Deshpande S, Wang A, Robb E bioRxiv. 2025; .

PMID: 40027628 PMC: 11870466. DOI: 10.1101/2025.02.18.638922.

Implications of gene × environment interactions in post-traumatic stress disorder risk and treatment.

Seah C, Sidamon-Eristoff A, Huckins L, Brennand K J Clin Invest. 2025; 135(5).

PMID: 40026250 PMC: 11870735. DOI: 10.1172/JCI185102.

References

Cederlof M, Thornton L, Baker J, Lichtenstein P, Larsson H, Ruck C . Etiological overlap between obsessive-compulsive disorder and anorexia nervosa: a longitudinal cohort, multigenerational family and twin study. World Psychiatry. 2015; 14(3):333-8. PMC: 4592656. DOI: 10.1002/wps.20251. View

Micali N, Martini M, Thomas J, Eddy K, Kothari R, Russell E . Lifetime and 12-month prevalence of eating disorders amongst women in mid-life: a population-based study of diagnoses and risk factors. BMC Med. 2017; 15(1):12. PMC: 5240354. DOI: 10.1186/s12916-016-0766-4. View

Yilmaz Z, Hardaway J, Bulik C . Genetics and Epigenetics of Eating Disorders. Adv Genomics Genet. 2016; 5:131-150. PMC: 4803116. DOI: 10.2147/AGG.S55776. View

Hubel C, Gaspar H, Coleman J, Finucane H, Purves K, Hanscombe K . Genomics of body fat percentage may contribute to sex bias in anorexia nervosa. Am J Med Genet B Neuropsychiatr Genet. 2018; 180(6):428-438. PMC: 6751355. DOI: 10.1002/ajmg.b.32709. View

Pickrell J, Berisa T, Liu J, Segurel L, Tung J, Hinds D . Detection and interpretation of shared genetic influences on 42 human traits. Nat Genet. 2016; 48(7):709-17. PMC: 5207801. DOI: 10.1038/ng.3570. View

Kirk K, Martin F, Mao A, Parker R, Maguire S, Thornton L . The Anorexia Nervosa Genetics Initiative: Study description and sample characteristics of the Australian and New Zealand arm. Aust N Z J Psychiatry. 2017; 51(6):583-594. DOI: 10.1177/0004867417700731. View

Ethier S, Miura H, Dostie J . Discovering genome regulation with 3C and 3C-related technologies. Biochim Biophys Acta. 2011; 1819(5):401-10. DOI: 10.1016/j.bbagrm.2011.12.004. View

Smemo S, Tena J, Kim K, Gamazon E, Sakabe N, Gomez-Marin C . Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature. 2014; 507(7492):371-5. PMC: 4113484. DOI: 10.1038/nature13138. View

Wright J, Brown S, Cole M . Upregulation of c-MYC in cis through a large chromatin loop linked to a cancer risk-associated single-nucleotide polymorphism in colorectal cancer cells. Mol Cell Biol. 2010; 30(6):1411-20. PMC: 2832500. DOI: 10.1128/MCB.01384-09. View

10.

Hudson J, Hiripi E, Pope Jr H, Kessler R . The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry. 2006; 61(3):348-58. PMC: 1892232. DOI: 10.1016/j.biopsych.2006.03.040. View

11.

Dekker J . Mapping the 3D genome: Aiming for consilience. Nat Rev Mol Cell Biol. 2016; 17(12):741-742. DOI: 10.1038/nrm.2016.151. View

12.

de Leeuw C, Mooij J, Heskes T, Posthuma D . MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015; 11(4):e1004219. PMC: 4401657. DOI: 10.1371/journal.pcbi.1004219. View

13.

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View

14.

Schaumberg K, Welch E, Breithaupt L, Hubel C, Baker J, Munn-Chernoff M . The Science Behind the Academy for Eating Disorders' Nine Truths About Eating Disorders. Eur Eat Disord Rev. 2017; 25(6):432-450. PMC: 5711426. DOI: 10.1002/erv.2553. View

15.

Keski-Rahkonen A, Mustelin L . Epidemiology of eating disorders in Europe: prevalence, incidence, comorbidity, course, consequences, and risk factors. Curr Opin Psychiatry. 2016; 29(6):340-5. DOI: 10.1097/YCO.0000000000000278. View

16.

Morris A, Voight B, Teslovich T, Ferreira T, V Segre A, Steinthorsdottir V . Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012; 44(9):981-90. PMC: 3442244. DOI: 10.1038/ng.2383. View

17.

Boraska V, Franklin C, Floyd J, Thornton L, Huckins L, Southam L . A genome-wide association study of anorexia nervosa. Mol Psychiatry. 2014; 19(10):1085-94. PMC: 4325090. DOI: 10.1038/mp.2013.187. View

18.

Euesden J, Lewis C, OReilly P . PRSice: Polygenic Risk Score software. Bioinformatics. 2015; 31(9):1466-8. PMC: 4410663. DOI: 10.1093/bioinformatics/btu848. View

19.

Moskvina V, Holmans P, Schmidt K, Craddock N . Design of case-controls studies with unscreened controls. Ann Hum Genet. 2005; 69(Pt 5):566-76. DOI: 10.1111/j.1529-8817.2005.00175.x. View

20.

Bulik-Sullivan B, Loh P, Finucane H, Ripke S, Yang J, Patterson N . LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015; 47(3):291-5. PMC: 4495769. DOI: 10.1038/ng.3211. View