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Familial co-aggregation and shared heritability between neurodevelopmental problems and cardiometabolic conditions

Nature Mental Health volume 3, pages 1545–1554 (2025)Cite this article

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Abstract

Neurodevelopmental conditions such as attention-deficit/hyperactivity disorder (ADHD) and autism co-occur with cardiometabolic conditions. However, little is known about the mechanisms underlying this co-occurrence. In this nationwide three-generation study using population-based registers in the Netherlands (n = 15 million), we assessed the familial (co-)aggregation of ADHD, autism and cardiometabolic conditions, and estimated their heritabilities and genetic correlations. ADHD, autism and cardiometabolic conditions showed aggregation and co-aggregation within families and between spouses. Estimated heritabilities of ADHD and autism were moderate (both h2 = 0.5), while those of cardiometabolic conditions ranged from low to moderate (h2 = 0.1–0.4). Genetic correlations between neurodevelopmental and cardiometabolic conditions were modest (rg = –0.02–0.20). Together, these results suggest a partly shared familial liability for neurodevelopmental and cardiometabolic conditions, and environmental factors likely play a more important role in the co-occurrence of neurodevelopmental and cardiometabolic conditions than genetics. These new insights can advance research toward specific etiological mechanisms and inform preventive strategies.

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Fig. 1: Familial aggregation of ADHD, autism and cardiometabolic conditions.
Fig. 2: Estimated heritability with 95% confidence intervals of ADHD, autism and cardiometabolic conditions.
Fig. 3: Familial co-aggregation of ADHD, autism and cardiometabolic conditions.
Fig. 4: Estimated genetic correlations with 95% confidence intervals between ADHD, autism and cardiometabolic conditions.

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Data availability

Under certain conditions, microdata from CBS are accessible for statistical and scientific research. For further information: microdata@cbs.nl.

Data of Lifelines may be obtained from a third party and are not publicly available. Researchers can apply to use the Lifelines data used in this study. More information about how to request Lifelines data and the conditions of use can be found on their website (https://www.lifelines-biobank.com/researchers/working-with-us).

Code availability

Code for the main analysis is publicly available at https://github.com/yiranli-hi/Familial-coaggregation-project (ref. 61).

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Acknowledgements

This research was supported by the European Union Horizon 2020 Research and Innovation Program (grant 956381 (C.A.H.)). This research reflects only the authors’ view, and the European Commission is not responsible for any use that may be made of the information it contains. This research used the data from the Lifelines cohort study. The Lifelines cohort study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Dutch Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Dutch Ministry of Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, the University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. Y.L. and Y.Z. acknowledge the support of a joint scholarship from the China Scholarship Council and the University of Groningen. M.B. acknowledges the support by NIMH grant R01MH125902. N.R.W. acknowledges the Australian National Health and Medical Research Council (1173790 and 1113400) and the Michael Davys Trust. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.

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Author notes

  1. These authors contributed equally: Yiran Li, Yiling Zhou.

  2. These authors jointly supervised this work: Catharina A. Hartman, Harold Snieder.

Authors and Affiliations

  1. Interdisciplinary Center Psychopathology and Emotion Regulation, Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

    Yiran Li, Melissa Vos, Martje Bos, Olivier Steen & Catharina A. Hartman

  2. Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

    Yiling Zhou & Harold Snieder

  3. Department of Psychiatry and Big Data Institute, University of Oxford, Oxford, UK

    Naomi R. Wray

  4. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

    Naomi R. Wray

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Contributions

Y.L. and Y.Z. conducted the data analyses. The study was conceptualized under the supervision of M.V., C.A.H. and H.S. Analysis code for the methods was originally developed by N.R.W. and M.B. and subsequently adapted by Y.L. and Y.Z. N.R.W. and M.B. provided additional methodological advice. O.S. performed the validation analyses using the Lifelines cohort. Y.L. and Y.Z. drafted the original paper. All authors reviewed the paper and contributed to its editing and revision.

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Correspondence to Yiran Li or Harold Snieder.

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Nature Mental Health thanks Joeri Meijsen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Li, Y., Zhou, Y., Vos, M. et al. Familial co-aggregation and shared heritability between neurodevelopmental problems and cardiometabolic conditions. Nat. Mental Health 3, 1545–1554 (2025). https://doi.org/10.1038/s44220-025-00535-y

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