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Influence of paternal age in schizophrenia

Pôle de psychiatrie du CHU de Créteil, groupe hospitalier Henri-Mondor-Albert-Chenevier, AP-HP, 40, rue Mesly, 94000 Créteil, France.
L Encéphale (Impact Factor: 0.6). 06/2011; 37(3):199-206. DOI: 10.1016/j.encep.2010.12.005
Source: PubMed

ABSTRACT Schizophrenia is an aetiologically heterogeneous syndrome, with a strong genetic component. Despite a reduced fertility in this disorder, its prevalence is maintained and could be explained by de novo genetic mutations. Advanced paternal age (APA) is a major source of new mutations in human beings and could thus be associated with an increased risk of developing schizophrenia in offspring. New mutations related to APA have been implicated as a cause of sporadic cases in several autosomal dominant diseases and also in neurodevelopmental diseases, autism, intellectual disabilities, and social functioning. The aim of the present study was to summarize the results of studies investigating the role of APA, and to discuss some interpretations.
All relevant studies were identified through the National Library of Medicine (PubMed(®) database). Keywords used for research were "age" and "schizophrenia" linked to "paternal or father". We have identified and analysed eight cohort studies, five case-control studies, two meta-analyses, and one review concerning different father's mutations potentially transmitted, two studies comparing paternal age at conception between sporadic versus familial cases of schizophrenia. All studies selected have been published between 2000 and 2009.
After controlling for several confounding factors including maternal age, the relative risk of schizophrenia increased from 1.84 to 4.62 in offspring of fathers with an older age of fatherhood. Mother's age showed no significant effects after adjusting for paternal age. There was a significant association between paternal age and risk of developing schizophrenia, there was a weaker association with psychosis.
The results of these different studies are confirmed by two recent meta-analyses which found an increased risk of schizophrenia in offspring of fathers older than 35 years. Two main hypotheses could explain these results. 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) [19], who found that patients without a family history of schizophrenia had significantly older fathers 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. The second hypothesis is based on the fact that fathers with schizophrenia spectrum personality disorder, known to be genetically related to schizophrenia, could have an advanced age at conception. However, regarding this hypothesis, advanced maternal age at conception should be a risk factor for schizophrenia, and this is not the case. Thus, the first hypothesis seems more plausible than the second. APA has been identified as a risk factor for other psychiatric disorders such as autism, bipolar disorder, obsessive-compulsive disorder, and phobia, and thus seems to be a non-specific risk factor. Furthermore, its association with impaired neurocognitive outcomes during infancy and childhood in normal populations raises the question of the phenotype linked to APA.
APA at conception appears to be a risk factor for schizophrenia. This risk factor probably interacts with genetic factors in a gene-environment interaction. To date, there is no validated cut-off at which the risk is significantly increased in offspring. In the future, studies could benefit from analyzing the phenotype related to APA.

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Available from: Andrei Szoke, Jul 09, 2015
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    • "Advanced parental age (APA) has been identified as a critical factor with regard to the development of distinct psychiatric pathologies such as schizophrenia and mood disorders in humans [1] [2] [3] [4]. This phenomenon becomes apparent either at advanced maternal or paternal age [5]. "
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    ABSTRACT: Increasing paternal age is known to be associated with a great variety of psychiatric disorders such as schizophrenia or autism. Hence the factor “age” may be taken as strategic tool to analyse specific scientific hypotheses. Additionally, this finding also needs to be addressed in rather pragmatically performed breeding protocols of model organisms, since otherwise artefacts may challenge the validity of the results.
    Physiology & Behavior 04/2015; 147. DOI:10.1016/j.physbeh.2015.04.041 · 3.03 Impact Factor
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    • "Illness risk is increased for relatives of probands, likely through rare genetic variants of large effect and common variants with small effects, which may interact with life course exposures to determine illness risk, although most cases have no family history (FH) of the disease (Svrakic et al. 2013). Another risk factor for schizophrenia is advanced paternal age (APA), demonstrated over a decade ago (Malaspina et al. 2001) and well replicated (Hubert et al. 2011). A study in the Icelandic cohort suggested that APA was related to schizophrenia risk through de novo mutations that increased in association with paternal aging (Kong et al. 2012). "
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    • "Illness risk is increased for relatives of probands, likely through rare genetic variants of large effect and common variants with small effects, which may interact with life course exposures to determine illness risk, although most cases have no family history (FH) of the disease (Svrakic et al. 2013). Another risk factor for schizophrenia is advanced paternal age (APA), demonstrated over a decade ago (Malaspina et al. 2001) and well replicated (Hubert et al. 2011). A study in the Icelandic cohort suggested that APA was related to schizophrenia risk through de novo mutations that increased in association with paternal aging (Kong et al. 2012). "
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    ABSTRACT: Leukocyte telomere length (LTL) is longer in association with advanced paternal age, but this association has not been examined along with family history (FH) in schizophrenia. LTL was measured by PCR and compared across cases and controls as part of a study to examine the characteristics of paternal age related schizophrenia. The 53 schizophrenia cases had similar mean LTL as 20 controls, although cases were significantly older than controls and overwhelmingly smoked cigarettes. Multivariate analyses showed that a FH of schizophrenia was associated with longer LTL in both male and female cases. Later paternal age was also related to longer LTL in male cases, but with shorter LTL in female cases. Male cases with older fathers and a FH had the longest LTL. The genetic architecture associated with a familial risk for schizophrenia may include pathways that lengthen LTL. Paternal aging conferred an additional increase in LTL lengthening in male cases, but reduced LTL in female cases. The gender difference in LTL for paternal aging is consistent with the severe illness features reported for female cases with older fathers and could implicate epigenetic alterations in the paternal X chromosomal region with advanced paternal age in association with the risk for schizophrenia.
    07/2014; 2(4). DOI:10.1002/mgg3.71
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