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Integrative GWAS identifies novel loci and genetic links between psychiatric and metabolic factors in anorexia nervosa

Molecular Psychiatry (2026)Cite this article

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Abstract

Anorexia nervosa (AN) is a complex psychiatric disorder with both psychiatric and metabolic underpinnings. This study aims to explore the genetic architecture of AN and the interplay between its psychiatric and metabolic components. Through a meta-analysis of AN GWAS data from European and Finnish populations, we identified a novel genome-wide significant locus near the SOX5 gene. Genetic correlation and Mendelian randomization analyses revealed shared and potentially causal relationships between AN and multiple psychiatric and metabolic traits. Local genetic correlation analysis identified 185 significant genomic regions contributing to shared heritability between AN and correlated phenotypes, with 100 loci demonstrating pleiotropic effects across multiple traits. The MTAG analyses identified 86 significant loci (34 overlapping with local genetic correlation results), including 25 novel loci such as brain-relevant VAMP2 (17p13.1) and metabolic-neurological hubs LPL (8p21.3) and BDNF (11p14.1). Gene Co-expression Network Analysis (WGCNA) further identified key gene modules associated with both metabolic and neurological pathways, particularly highlighting synaptic signaling and lipid metabolism. Single-cell transcriptomic analysis further resolved this genetic risk to the cellular level, confirming its concentration in limbic and striatal GABAergic neurons and extending the implicated circuitry to include cortical regions involved in motor function. These findings collectively demonstrate the intricate genetic interplay between psychiatric and metabolic pathways in AN, underscoring the necessity of an integrated approach to understanding its pathogenesis.

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Fig. 1: Schematic workflow of the integrative multi-tiered analysis for anorexia nervosa.
Fig. 2: Genetic correlation network between anorexia nervosa and risk factors.
Fig. 3: Distribution of the significant local-level genetic correlation between anorexia nervosa and genetically correlated traits across the genomic landscape of chromosomes.
Fig. 4: Manhattan plot of the GWAS multi-trait meta-analysis between anorexia nervosa and psychiatric traits.
Fig. 5: Cell-type and brain-region mapping of anorexia nervosa polygenic enrichment using scDRS.

Data availability

The GWAS summary statistics for AN were obtained from the Psychiatric Genomics Consortium (PGC) website (https://pgc.unc.edu/for-researchers/download-results/). The GWAS summary statistics for risk factors in Europeans were sourced from the Neale Lab UK Biobank GWAS web browser (http://www.nealelab.is/uk-biobank/). The GWAS summary statistics for AN and risk factors in the Finnish population were derived from the FinnGen consortium (https://r10.finngen.fi/).

Code availability

The code used in the present study is available in public repositories: plink (https://github.com/ chrchang/plink-ng), LDSC/S-LDSC (https://github.com/bulik/ldsc), TwoSampleMR (https://mrcieu.github.io/TwoSampleMR), LAVA (https://github.com/josefin-werme/LAVA), MTAG (https://github.com/JonJala/mtag), S‑PrediXcan/S‑MultiXcan (https://github.com/ hakyimlab/MetaXcan), WGCNA (https://cran.r-project.org/web/packages/WGCNA), g:Profiler (https://biit.cs.ut.ee/gprofiler/gost) and scDRS (https://github.com/martinjzhang/scDRS).

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Acknowledgements

The study was supported by grants from the Special Funds of Taishan Scholar Project, China (tsqn202211224), the National Natural Science Foundation of China (32270661), Excellent Youth Science Fund Project (Overseas) of Shandong China (2023HWYQ-082), the China Postdoctoral Science Foundation (2024M761870), Shandong Postdoctoral Science Foundation (SDCX-ZG-202400042) and Shandong Province Higher Education Institution Youth Innovation and Technology Support Program (2023KJ179).

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  1. These authors contributed equally: Yingchao Song, Yue Jiang.

Authors and Affiliations

  1. College of Medical Information and Artificial Intelligence, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Yingchao Song, Yue Jiang & Xiao Chang

  2. Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China

    He Tian & Xiao Chang

  3. Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Joseph Glessner & Hakon Hakonarson

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  1. Yingchao Song
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Contributions

XC and HH conceptualized and designed the study; YCS and YJ collected the data; YCS and YJ analyzed the data; HT and JG performed the validation analyses; YCS and YJ drafted the manuscript, XC and HH revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hakon Hakonarson or Xiao Chang.

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This study used only publicly available summary-level data from previously published studies. No individual-level data were accessed and no new human or animal subjects were involved. All analyses were conducted in accordance with relevant guidelines and regulations. Ethical approval and informed consent were therefore not required.

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Song, Y., Jiang, Y., Tian, H. et al. Integrative GWAS identifies novel loci and genetic links between psychiatric and metabolic factors in anorexia nervosa. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03591-7

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