Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche.
A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed which included 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at onset, early-onset AN (< 13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.
Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (SNP-h2) were 0.01-0.04 for age at onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age at onset and early-onset AN estimated from independent GWASs significantly predicted age at onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN.
Our results provide evidence consistent with a common variant genetic basis for age at onset and implicate biological pathways regulating menarche and reproduction.
We are deeply thankful to the thousands of individuals who contributed their time and biological samples, and to the many collaborators who helped to collate these samples over the years. We are extremely grateful to members of the Eating Disorders Working Group of the Psychiatric Genomics Consortium for their contributions, efforts, and leadership (Appendix). The Psychiatric Genomics Consortium is supported by funding from the National Institute of Mental Health (U01MH109528, U01MH109514). We are grateful to the Anorexia Nervosa Genetics Initiative (ANGI), which is an initiative of the Klarman Family Foundation. We thank the Children’s Hospital of Philadelphia (CHOP), the Price Foundation Collaborative Group (PFCG), Genetic Consortium for Anorexia Nervosa (GCAN), and the Wellcome Trust Case-Control Consortium-3 (WTCCC3). We would also like to thank the Stockholm Centre for Eating Disorders (SCÄ), the Swedish National Quality Register for Eating Disorders (Riksät), and Lifegene for their support of ANGI Sweden. We thank the QSkin Sun and Health Study for control samples. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. This content is the responsibility of the authors and does not represent the views of the funding bodies.
Data Availability StatementSupplementary material cited in this article is available online at https://doi.org/10.1016/j.bpsgos.2021.09.001.
- age at onset
- anorexia nervosa
- genetic risk score
- Mendelian randomization