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Paternal age and 13 psychiatric disorders in the offspring: a population-based cohort study of 7 million children in Taiwan

Molecular Psychiatry volume 27, pages 5244–5254 (2022)Cite this article

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Abstract

Although paternal age has been linked to certain psychiatric disorders, the nature of any causal relationship remains elusive. Here, we aimed to comprehensively assess the magnitude of a wide range of offspring’s psychiatric risk conferred by paternal age, leveraging a pedigree inferred from covered-insurance relationship (accuracy >98%) in Taiwan’s single-payer compulsory insurance program. We also examined whether there is an independent role of paternal age and explored the potential effect of parental age difference. A total cohort of 7,264,788 individuals born between 1980 and 2018 were included; 5,572,232 with sibling(s) were selected for sibling-comparison analyses and 1,368,942 and 1,044,420 children with information of paternal-grandparents and maternal-grandparents, respectively, were selected for multi-generation analyses. Using inpatient/outpatient claims data (1997–2018), we identified schizophrenia, autism, bipolar disorder (BPD), attention deficit-hyperactivity disorder (ADHD), major depressive disorder (MDD), eating disorder (ED), substance use disorder (SUD), mental retardation (MR), tic disorder, obsessive-compulsive disorder (OCD), anxiety, and somatoform disorder. We identified suicides using death certificates. Logistic regression analysis was used to estimate the paternal/maternal/grand-paternal age association with psychiatric risk in the offspring. The total cohort and sibling-comparison cohort resulted in similar estimates. Paternal age had a U-shaped relationship with offspring’s MDD, ED, SUD, and anxiety. A very young maternal age (<20 years) was associated with markedly higher risk in offspring’s SUD, MR, and suicide. Older paternal age (>25 years) was linearly associated with offspring’s schizophrenia, autism, BPD, ADHD, MDD, ED, SUD, MR, OCD, anxiety, and suicide. Older grand-paternal age was linearly associated with offspring’s schizophrenia, autism, ADHD, and MR. Dissimilar parental age was positively associated with offspring’s ADHD, MDD, SUD, MR, anxiety, and suicide, and negatively associated with offspring’s OCD. This comprehensive assessment provides solid evidence for the independent role of paternal age in psychiatric risk in the offspring and clarifies the significance of both early parenthood and delayed paternity.

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Fig. 1: Cumulative incidence of 13 psychiatric disorders in offspring of paternal age groups of 25–29 and of ≥50, and attributable risk of 13 psychiatric disorders in offspring due to advanced paternal age ≥50.
Fig. 2: Associations between parental age and offspring psychiatric risk in the total cohort and the sibling-comparison cohort.
Fig. 3: Associations between paternal- and maternal- grandfather and grandmother age and offspring psychiatric risk in the multi-generational analyses.
Fig. 4: The joint association of paternal age and maternal age with offspring psychiatric risk.

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Acknowledgements

This study was approved by the Central Regional Research Ethics Committee of the China Medical University, Taichung, Taiwan (CRREC-108-28). The requirement for informed consent was waived because the NHIRD consists of de-identified data. The NHIRD used in this study is held by the Taiwan Ministry of Health and Welfare. The Ministry of Health and Welfare approved our application to access these data.

Funding

This study was supported by Taiwan Ministry of Science and Technology (MOST 106-2314-B-039-052-MY2; MOST 108-2314-B-039-030-MY3), and China Medical University (CMU108-MF-57; CMU109-MF-74; CMU110-MF-79). CCF was supported by grant R01MH122688 and RF1MH120025 funded by the National Institute for Mental Health (NIMH).

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Authors and Affiliations

  1. Department of Occupational Safety and Health, College of Public Health, China Medical University, Taichung, Taiwan

    Shi-Heng Wang & Mei-Chen Lin

  2. Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan

    Shi-Heng Wang & Pei-Chun Chen

  3. Interdisciplinary Freshmen Program of Public Health, College of Public Health, China Medical University, Taichung, Taiwan

    Shi-Heng Wang & Mei-Chen Lin

  4. National Center for Geriatrics and Welfare Research, National Health Research Institutes, Miaoli, Taiwan

    Chi-Shin Wu

  5. Department of Psychiatry, National Taiwan University Hospital, Yunlin branch, Douliu, Taiwan

    Chi-Shin Wu

  6. Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan

    Le-Yin Hsu

  7. Graduate Program of Data Science, National Taiwan University and Academia Sinica, Taipei, Taiwan

    Le-Yin Hsu

  8. Center for Population Neuroscience and Genetics, Laureate Institute for Brain Research, Tulsa, OK, USA

    Wesley K. Thompson & Chun-Chieh Fan

  9. Department of Radiology, School of Medicine, University of California San Diego, La Jolla, CA, USA

    Chun-Chieh Fan

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Contributions

SHW initiated and designed the study, and drafted the manuscript. SHW, LYH and MCL analyzed the data. CSW, PCC, WKT, and CCF interpreted the data and criticized the manuscript for important intellectual content. All the authors approved the final version of the manuscript.

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Wang, SH., Wu, CS., Hsu, LY. et al. Paternal age and 13 psychiatric disorders in the offspring: a population-based cohort study of 7 million children in Taiwan. Mol Psychiatry 27, 5244–5254 (2022). https://doi.org/10.1038/s41380-022-01753-x

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