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Genome-wide significant risk loci for mood disorders in the Old Order Amish founder population

Molecular Psychiatry volume 28, pages 5262–5271 (2023)Cite this article

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Abstract

Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n = 1,672). Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n = 314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors, CUX1 and CNOT1. Our findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies.

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Fig. 1: Discovery of four genome-wide significant risk loci for mood disorders in the Old Order Amish founder population (n = 1672).
Fig. 2: OOA-specific risk alleles for mood disorders are associated with depressive symptoms and cognitive performance.
Fig. 3: Genes at OOA-specific risk loci for mood disorders interact with neuropsychiatry-related gene networks.

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Acknowledgements

This study was supported by grants and contracts from the National Institute of Mental Health (U01 MH108148 to LEH and PK, R01 MH110437 to PPZ, U01 MH105630 to DCG, U01 MH105632 to JB, R01 MH129343 to SAA, R01 MH093415 to M.B. and Steven. M. Paul), the Regeneron Genetics Center, the Intramural Research Program of the National Institute of Mental Health (ZIA MH002843 to FJM), and a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation to SAA Most of all, we thank the Amish and Mennonite participants, without whose longstanding partnership this study would not have been possible.

Author information

Authors and Affiliations

  1. Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA

    Elizabeth M. Humphries, Evelina Mocci & Seth A. Ament

  2. Program in Molecular Epidemiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Elizabeth M. Humphries

  3. Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA

    Kwangmi Ahn, Fabiana L. Lopes & Francis J. McMahon

  4. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    Rachel L. Kember

  5. University of Texas Rio Grande Valley, Harlingen, TX, USA

    Juan M. Peralta & John Blangero

  6. Boston Children’s Hospital, Boston, MA, USA

    David C. Glahn

  7. Departments of Epidemiology and Mental Health, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Fernando S. Goes

  8. Departments of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Peter P. Zandi

  9. Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA

    Peter Kochunov, L. Elliot Hong & Seth A. Ament

  10. Regeneron Genetics Center, Tarrytown, NY, USA

    Cristopher Van Hout & Alan R. Shuldiner

  11. Laboratorio Internacional de Investigatión sobre el Genoma Humano, Campus Juriquilla de la Universidad Nacional Autónoma de México, Querétaro, Querétaro, 76230, Mexico

    Cristopher Van Hout

  12. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Alan R. Shuldiner, Toni I. Pollin & Braxton D. Mitchell

  13. Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Alan R. Shuldiner, Toni I. Pollin & Braxton D. Mitchell

  14. Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA

    Maja Bucan

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  1. Elizabeth M. Humphries
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Contributions

Conceptualization – EMH, MB, LEH, FJM, SAA. Formal analysis – EMH, KA, RLK, FLL, EM, JMP, SAA. Resources – JB, DCG, FSG, PPZ, PK, CVH, ARS, TIP, BDM, MB, LEH, FJM. Supervision – BDM, MB, LEH, FJM, SAA. Funding Acquisition – JB, DCG, PPZ, PK, ARS, TIP, BDM, MB, LEH, FJM, SAA. Writing (Original Draft) – EMH, SAA. Writing (review and editing) – All authors.

Corresponding author

Correspondence to Seth A. Ament.

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Competing interests

ARS is an employee of Regeneron Pharmaceuticals. LEH has received or plans to receive research funding or consulting fees on research projects from Mitsubishi, Your Energy Systems LLC, Neuralstem, Taisho, Heptares, Pfizer, Sound Pharma, IGC Pharma, Regeneron, and Takeda. SAA has received research funding from Oryzon Genomics LLC. All other authors declare no biomedical financial interests or potential competing interests.

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Humphries, E.M., Ahn, K., Kember, R.L. et al. Genome-wide significant risk loci for mood disorders in the Old Order Amish founder population. Mol Psychiatry 28, 5262–5271 (2023). https://doi.org/10.1038/s41380-023-02014-1

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