Paternal age and sporadic schizophrenia: Evidence for de novo mutations

Abstract

Schizophrenia is an etiologically heterogeneous syndrome. It has a strong genetic component and exists in clinically indistinguishable familial and nonfamilial (sporadic) forms. A significant role for de novo genetic mutations in genetic schizophrenia vulnerability is suggested by a strong monotonic increase in schizophrenia risk with advancing paternal age. However, an alternative explanation for the paternal age effect in schizophrenia is that childbearing is delayed in fathers who themselves have genetic schizophrenia vulnerability. In this study, we compared paternal birth ages between patient groups with familial (n = 35) and sporadic (n = 68) patients with DSM-IV schizophrenia from an inpatient schizophrenia research unit. If later age of fathering children is related to having some genetic schizophrenia vulnerability, then paternal birth age should be later in familial schizophrenia cases than in sporadic cases, and any association of father's age and schizophrenia risk in offspring would be a spurious finding, unrelated to etiology. However, if de novo mutations cause sporadic schizophrenia, then patients without a family history of schizophrenia would have older fathers than familial patients. We found that patients without a family history of schizophrenia had significantly older fathers (4.7 years) than familial patients; so later childbirth was not attributable to parental psychiatric illness. These findings support the hypothesis that de novo mutations contribute to the risk for sporadic schizophrenia.

Sexual Selection for Moral Virtues

“…Also, since mutation load in sperm increases dramatically as men age (Crow 2000), all else being equal, younger fathers should sire more virtuous children. Such paternal age effects have been shown for various virtue-reducing mental illnesses, such as schizophrenia (Malaspina et al 2002;Byrne et al 2003) and autism (Reichenberg et al 2006). Future research could use similar methods to investigate other virtues more directly.…”

Effects of age on DNA double-strand breaks and apoptosis in human sperm

“…However, there are many environmental factors that may be responsible for observed decreases in sperm quality, independent of age, and that may have significant reproductive consequences, including birth defects (95), cancer (96 -98), and mental disorders (99) in offspring. These environmental insults include cigarette smoking (97, 100), consumption of alcohol (98), and caffeine intake (101).…”

Influence of Paternal Age in Schizophrenia

“…The first one is based on the presence of new mutations in the spermatogonia, possibly because of accumulating replication errors in spermatogonial cell lines. This hypothesis is confirmed by Malaspina et al (2002), which found that patients without a family history of schizophrenia had significantly older father than probands with a positive family history of schizophrenia. However, this result has not been confirmed by other studies, and paternal age effect could be also explained by a mechanism called imprinting, which is a form of gene regulation.…”

“…Cette hypothèse est corroborée par plusieurs études montrant que l"âge moyen du père dans les formes sporadiques est plus élevé que dans les formes familiales [19], même si ces résultats ne sont pas toujours confirmés [7,38,42].…”

“…Ils ne montrent pas de corrélation entre âge paternel et pathologie schizophrénique chez les apparentés, ni entre âge paternel et antécédents familiaux. Ces résultats ne confirment donc pas ceux obtenus par Malaspina et al, [19] et pourraient être dus à une hétérogénéité clinique des groupes de sujets inclus dans les deux études.…”