Advanced paternal age and risk of schizophrenia in offspring – Review of epidemiological findings and potential mechanisms

Impact of paternal age on assisted reproductive technology outcomes and offspring health: a systematic review

“…About the underlying mechanisms, several hypotheses have been proposed: the first hypothesis is an increase of de novo mutations with paternal age, explained by the fact that spermatogonial mitoses persist throughout a man's life, unlike ovogonial mitoses, which occur early, entirely during fetal life. But once again, the de novo mutation rate could not entirely explain the correlation between paternal age and psychiatric disorders 19,82,83 . The second hypothesis is epigenetic: the significantly low level of DNA methylation through time in spermatogonia, especially of some gene promoters, would allow the expression of repressed genes 80,84 .…”

“…But once again, the de novo mutation rate could not entirely explain the correlation between paternal age and psychiatric disorders. 19,82,83 The second hypothesis is epigenetic: the significantly low level of DNA methylation through time in spermatogonia, especially of some gene promoters, would allow the expression of repressed genes. 80,84 Some authors alert that the alteration of this genetic imprinting could also be transmitted to the next generation, even if the demonstration of this transgenerational transmission is not yet established.…”

The impact of paternal age on new mutations and disease in the next generation

“…There is considerable debate as to whether the link between advanced paternal age and these disorders is due to: inherited genetic factors influencing the health of fathers and timing of reproduction (inherited model); testes-driven DNMs that arise randomly as a consequence of aging (de novo model); environmental factors (such as oxidative stress); epigenetic factors that accumulate over time; or (more likely) a combination of the above (12,50,(83)(84)(85)(86)(87)(88). Unraveling the contribution of these factors to the PAE in common disorders is challenging (and beyond the scope of this review), but before this can be attempted, a better understanding of the etiology of these ''complex'' disorders will be required (12,89). For example, Yoon et al ( 87) recently showed that stratification of autism into two subtypes (simplex/low-risk families with a single affected child vs. multiplex/high risk with recurrent family history), provides an efficient way to identify families with likely causative de novo events, where they contribute to autism risk in up to 70% of the low-risk families.…”

“…There is considerable debate as to whether the link between advanced paternal age and these disorders is due to: inherited genetic factors influencing the health of fathers and timing of reproduction (inherited model); testes-driven DNMs that arise randomly as a consequence of aging (de novo model); environmental factors (such as oxidative stress); epigenetic factors that accumulate over time; or (more likely) a combination of the above ( 12 , 50 , 83 , 84 , 85 , 86 , 87 , 88 ). Unraveling the contribution of these factors to the PAE in common disorders is challenging (and beyond the scope of this review), but before this can be attempted, a better understanding of the etiology of these “complex” disorders will be required ( 12 , 89 ). For example, Yoon et al.…”

Reproductive axis ageing and fertility in men

“…In summary, while genetic defects related to faulty sperm quality control leading to single gene mutations and epigenetic and methylation alterations have been implicated as root causes affecting offspring health, exact mechanistic understanding remains to be clarified [ 127 ]. The precise paternal age at which risk develops and the magnitude of the risk are also poorly understood or may have gradual effects [ 128 ], although overall, the RR for psychiatric conditions is in the range of 1.5–5.7 and that for single gene disorders is 1.3–12 with paternal age > 40 years [ 118 ].…”