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Exposomic and polygenic contributions to allostatic load in early adolescence

Nature Mental Health volume 2, pages 828–839 (2024)Cite this article

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Abstract

Allostatic load (AL) is the cumulative ‘wear and tear’ on the body due to chronic adversity. We tested the poly-environmental (exposomic) and polygenic contributions to AL and their combined contribution to adolescent mental health. In this cohort study of N = 5,036 diverse youth (mean age 12 years) from the Adolescent Brain Cognitive Development Study, we calculated a latent AL score, childhood exposomic risk and genetic risk. We tested the associations of exposomic and polygenic risks with AL using linear mixed-effects models, and tested the mediating role of AL on the pathway from exposomic/polygenic risk to mental health. AL was significantly lower among non-Hispanic white youth compared to Hispanic and non-Hispanic black youth. Childhood exposomic burden was associated with AL in adolescence (β = 0.25, 95% CI 0.22–0.29, P < 0.001). In subset analysis of participants of European-like genetic ancestry (n = 2,928), the type 2 diabetes polygenic risk score (T2D-PRS; β = 0.11, 95% CI 0.07–0.14, P < 0.001) and major depressive disorder (MDD)-PRS (β = 0.05, 95% CI 0.02–0.09, P = 0.003) were associated with AL. Both PRSs showed significant gene–environment interactions such that, with greater polygenic risk, associations between exposome and AL were stronger. AL significantly mediated the indirect path from exposomic risk at age 11 years, and from both MDD-PRS and T2D-PRS to psychopathology at age 12 years. Our findings show that AL can be quantified in youth and is associated with exposomic and polygenic burden, supporting the diathesis–stress model.

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Fig. 1: Conceptual study design.
Fig. 2: Allostatic load quantification in the ABCD Study.
Fig. 3: Association of exposomic burden with AL and demographic differences.
Fig. 4: Gene–environment interaction in AL.
Fig. 5: Mediation of AL on the paths from exposomic and polygenic risk to mental-health burden.

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Data availability

Data used in the preparation of this Article were obtained from the ABCD Study (https://abcdstudy.org), held in the National Institute of Mental Health Data Archive and available for researchers upon application (https://nda.nih.gov/abcd/request-access).

Code availability

Code is available at https://github.com/barzilab1/ABCD_Allostatic_load.

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Acknowledgements

Data used in the preparation of this article were obtained from the ABCD Study (https://abcdstudy.org), held in the NDA. This is a multisite, longitudinal study designed to recruit more than 10,000 children age 9–10 and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123 and U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in the analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the National Institutes of Health or ABCD consortium investigators. R.B. is supported by the National Institute of Mental Health (K23MH120437). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. A draft of this manuscript has been posted as a preprint on medRxiv (https://doi.org/10.1101/2023.10.27.23297674v1).

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Authors and Affiliations

  1. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Kevin W. Hoffman, Tyler M. Moore, Matthew R. Hayes & Ran Barzilay

  2. Department of Child and Adolescent Psychiatry and Behavioral Science, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Kevin W. Hoffman & Ran Barzilay

  3. Lifespan Brain Institute of Children’s Hospital of Philadelphia and Penn Medicine, Philadelphia, PA, USA

    Kate T. Tran, Tyler M. Moore, Mārtiņš M. Gataviņš, Elina Visoki, Ohyoon Kwon, Grace E. DiDomenico, Barbara H. Chaiyachati, Laura M. Schultz, Laura Almasy & Ran Barzilay

  4. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Ohyoon Kwon & Barbara H. Chaiyachati

  5. PolicyLab, Clinical Futures, Division of General Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Barbara H. Chaiyachati

  6. Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Laura M. Schultz & Laura Almasy

  7. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Laura Almasy

  8. Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA

    Nikolaos P. Daskalakis

  9. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Nikolaos P. Daskalakis

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  1. Kevin W. Hoffman
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Contributions

K.W.H., T.M.M., M.M.G., O.K. and R.B. conceived and designed the study. K.T.T., E.V., G.E.D. and L.M.S. curated and organized the data. K.T.T., T.M.M., E.V. and L.M.S. analyzed the data. B.H.C., L.A., M.R.H. and N.P.D. substantially contributed to interpretation of the data. K.W.H., K.T.T. and R.B. wrote the first draft of the manuscript. M.M.G., O.K., B.H.C., L.M.S., L.A., M.R.H. and N.P.D. substantially revised the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Ran Barzilay.

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Competing interests

R.B. serves on the Scientific Advisory Board and holds equity in Taliaz Health, with no relevance to this work. The remaining authors declare no competing interests.

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Nature Mental Health thanks Zhiyang Wang and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Supplementary Tables 1–8 and Fig. 1.

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Hoffman, K.W., Tran, K.T., Moore, T.M. et al. Exposomic and polygenic contributions to allostatic load in early adolescence. Nat. Mental Health 2, 828–839 (2024). https://doi.org/10.1038/s44220-024-00255-9

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