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Paternal age, de novo mutation, and age at onset among co-affected schizophrenia sib-pairs: whole-genome sequencing in multiplex families

Abstract

Whether delaying fatherhood leads to more mutations, thereby resulting in adverse psychiatric outcomes in offspring, remains under debate. No study has directly examined the role of de novo mutations (DNMs) between paternal age and offspring psychiatric outcomes. This study aimed to explore the association between paternal age, the number of DNMs, and age at onset of schizophrenia by sequencing the whole genome of multiplex schizophrenia families. Whole-genome sequencing (30x) was performed in 5 Taiwanese families, each comprising 3 co-affected siblings and healthy parents. Causal mediation analyses were used to explore the mediating role of DNMs in the paternal age effect. Paternal age predicted increased DNMs (+1.50 DNMs/year, 95% CI: 0.81, 2.19, p < 0.0001) over maternal age (+0.09 DNMs/year, 95% CI: −1.01, 1.19, p = 0.87). The effect of paternal age on the number of DNMs varied across families. Each additional DNM resulted in a 0.16-year earlier onset age of schizophrenia (95% CI: 0.04, 0.27, p = 0.009). The estimated direct effect of paternal age on the onset of schizophrenia was −0.82 (95% CI: −0.90, −0.73), while the indirect effect through DNMs was −0.32 (95% CI: −0.47, −0.17). The proportion mediated via DNMs was 28.04% (95% CI: 18.19%, 37.89%). The mediation analyses showed that 30% of the observed association of paternal age with onset age of schizophrenia might be mediated through paternal age-related DNMs. Our study, the first to directly quantify the mediating effect of DNMs, provides support for a causal role of paternal age-related mutations in the increased psychiatric risk in offspring.

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Fig. 1: Pedigrees of the whole-genome sequenced families.
Fig. 2: Parental age and the onset age of schizophrenia.
Fig. 3: Parental age and the number of de novo mutations (DNMs).
Fig. 4
Fig. 5

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Data availability

The data that support the findings of this study are not publicly available due to conditions in the participant consent and other ethical restrictions.

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Funding

This study was supported by the Taiwan Ministry of Science and Technology (MOST 106-2314-B-039-052-MY2; MOST 108-2314-B-039-030-MY3) and National Science and Technology Council (NSTC112-2628-B-400-003-MY3). Y.A.F acknowledged support from the NSTC (NSTC 112-2314-B-002-200-MY3) and the Yushan Young Fellow Program provided by the Ministry of Education (MOE; NTU-112V1020-2).

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SHW initiated and designed the study. YCF and SHW drafted the manuscript. YCF, MCL, CFC, and SHW analyzed the data. WJC, JSH, CML, HWH, YTH, and TPL interpreted the data and criticised the manuscript for important intellectual content. All the authors approved the final version of the manuscript.

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Correspondence to Wei J. Chen or Shi-Heng Wang.

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Methods were carried out in accordance with the relevant guidelines and regulations. This study was approved by the National Taiwan University Hospital Research Ethics Committee (201709030RIN). Informed consent was obtained from all participants.

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Feng, YC.A., Chen, W.J., Lin, MC. et al. Paternal age, de novo mutation, and age at onset among co-affected schizophrenia sib-pairs: whole-genome sequencing in multiplex families. Mol Psychiatry 30, 3560–3567 (2025). https://doi.org/10.1038/s41380-025-02942-0

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