Opposite differential risks for autism and schizophrenia based on maternal age, paternal age, and parental age differences

Jacobus J. Boomsma,Sean G. Byars

doi:10.1093/emph/eow023

Abstract

Effects of maternal and paternal age on offspring autism and schizophrenia risks have been studied for over three decades, but inconsistent risks have often been found, precluding well-informed speculation on why these age-related risks might exist. To help clarify this situation we analysed a massive single population sample from Denmark including the full spectrum of autistic and schizophrenic disorders (eliminating between-study confounding), used up to 30 follow-up years, controlled for over 20 potentially confounding factors and interpret the ultimate causation of the observed risk patterns using generally accepted principles of parent-offspring conflict and life-history theory. We evaluated the effects of paternal age, maternal age and parental age difference on offspring mental disorders and found consistently similar risk patterns for related disorders and markedly different patterns between autistic and schizophrenic disorders. Older fathers and mothers both conferred increased risk for autistic but not schizophrenic disorders, but autism risk was reduced in younger parents and offspring of younger mothers had increased risk for many schizophrenic disorders. Risk for most disorders also increased when parents were more dissimilarly aged. Monotonically increasing autism risk is consistent with mutation accumulation as fathers' age, but this explanation is invalid for schizophrenic disorders, which were not related to paternal age and were negatively correlated with maternal age. We propose that the observed maternally induced risk patterns ultimately reflect a shifting ancestral life-history trade-off between current and future reproduction, mediated by an initially high but subsequently decreasing tendency to constrain foetal provisioning as women proceed from first to final pregnancy.

Highlights

Since the first single-disorder surveys that discovered an association between risk of autism or schizophrenia and advancing maternal or paternal age over 30 years ago [1, 2], there have been numerous studies that have attempted to confirm this pattern, including several very recent ones [3,4,5,6]
McGrath et al [6] and others [3, 7] found that autism risk was significantly higher for offspring born to older fathers, while Lampi et al [5] and Lundstrom et al [9] found significant U-shaped risk patterns
Above-average paternal and maternal ages were consistently associated with increased risk of most autistic disorders in offspring (Fig. 1A and B). This effect was magnified in offspring of very old fathers and mothers as risk continued to increase in age groups further from the reference group

Summary

Introduction

Since the first single-disorder surveys that discovered an association between risk of autism or schizophrenia and advancing maternal or paternal age over 30 years ago [1, 2], there have been numerous studies that have attempted to confirm this pattern, including several very recent ones [3,4,5,6]. Despite this substantial effort, risk patterns for the same disorders have been found to be highly variable and results often remain incomparable due to substantial differences in study design (Supplementary Table S1).

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Conclusion