Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes During Infancy and Childhood

Sukanta Saha; Adrian G. Barnett; Claire Foldi; Thomas H. Burne; Darryl W. Eyles; Stephen L. Buka; John J. McGrath

Disclosures

PLoS Med. 2009;6(3):e1000040 

In This Article

Abstract and Introduction

Abstract

Background: Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia, as well as with dyslexia and reduced intelligence. The aim of this study was to examine the relationship between paternal age and performance on neurocognitive measures during infancy and childhood.
Methods and Findings: A sample of singleton children (n = 33,437) was drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 8 mo, 4 y, and 7 y (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test). The main analyses examined the relationship between neurocognitive measures and paternal or maternal age when adjusted for potential confounding factors. Advanced paternal age showed significant associations with poorer scores on all of the neurocognitive measures apart from the Bayley Motor score. The findings were broadly consistent in direction and effect size at all three ages. In contrast, advanced maternal age was generally associated with better scores on these same measures.
Conclusions: The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood. In light of secular trends related to delayed fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.

Introduction

In recent decades there has been increased attention to health outcomes in the offspring of older fathers. Evidence shows that advanced paternal age (APA) is associated with an increased risk of a wide range of disorders.[1] While not discounting the influence of various age-related psychosocial factors that may translate to differential health outcomes for the offspring of older fathers (e.g., higher socioeconomic status, better education), advances in genomics have refocused attention on the vulnerability of sperm from older fathers to carrying de novo mutations. The development of the germ cell differs between human males and females -- there are many more germline cell divisions in the life history of a sperm relative to that of an oocyte.[2] In the female there are 22 mitotic cell divisions that occur in utero. In contrast, after puberty, progenitor sperm stem cells undergo mitotic cell division once every 16 d. By age 20 the progenitor sperm cells have undergone approximately 150 cell divisions. By age 50 this number is 840. Thus, the chance of copy error mutations increases with age in males more dramatically than for females.

Advanced paternal age is associated with increased fetal deaths[3,4] and certain rare congenital syndromes (e.g., achondroplasia).[1,5] In recent years evidence has accumulated linking APA with a wide range of neurological and neuropsychiatric conditions including Alzheimer's disease,[6,7] bipolar disorder,[8] dyslexia,[9] neural tube defects,[10] and epilepsy.[11] A sizeable body of evidence has accumulated linking APA with an increased risk of schizophrenia.[12,13,14,15,16,17,18] A recent meta-analysis based on eight studies found that paternal age above 35 was associated with an increased risk of schizophrenia.[19] There is also evidence linking APA to autism spectrum disorders.[20,21,22,23,24]

The associations between APA and outcomes such as autism and schizophrenia are of particular interest, as these disorders have recently been associated with genomic structural variation.[25,26,27,28,29,30] It is feasible that APA-related mechanisms may contribute to genomic structural variation (e.g., copy number variants, microdeletions).[2] Thus, within the fields of schizophrenia and autism research, there has been an unexpected convergence between epidemiology and molecular biology.

While there is good evidence linking paternal age with several clinically distinct neurodevelopmental disorders, the evidence linking paternal age and other neurocognitive outcomes such as general intelligence is less robust. Earlier studies noted an association between APA and poorer performance on neurocognitive tests.[31,32,33,34] This issue has been addressed specifically in a recent study based on male and female Israeli conscripts (age 16-17 y, n = 44,175).[35] The study found independent effects of paternal age on offspring intelligence with the lowest scores associated with both younger and older fathers (inverted "U"-shaped association). This finding is in contrast to the association between maternal age and offspring intelligence, where most studies have reported a linear association between older maternal age and superior neurocognitive ability.[36,37,38,39]

The aim of the present study was to explore the association between paternal age and a range of neurocognitive measures using a large, prospective birth cohort: the US-based Collaborative Perinatal Project (CPP). Based on the literature linking increased paternal age with a range of developmental anomalies and neuropsychiatric disorders, we hypothesized that the children of older fathers would have lower scores on various tests used to measure neurocognitive ability when assessed at 8 mo, 4 y, and 7 y. While a study based on this same cohort had previously identified that the offspring of older mothers had superior performance on neurocognitive functioning,[36] we also took the opportunity to re-examine this hypothesis in the current analyses.

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