Parental and grandparental ages in the autistic spectrum disorders: a birth cohort study

Abstract

Background: A number of studies have assessed ages of parents of children with autistic spectrum disorders (ASD), and reported both maternal and paternal age effects. Here we assess relationships with grandparental ages.

Methods and findings: We compared the parental and grandparental ages of children in the population-based Avon Longitudinal Study of Parents and Children (ALSPAC), according to their scores in regard to 4 autistic trait measures and whether they had been given a diagnosis of ASD. Mean maternal and paternal ages of ASD cases were raised, but this appears to be secondary to a maternal grandmother age effect (P = 0.006): OR = 1.66[95%CI 1.16, 2.37] for each 10-year increase in the grandmother's age at the birth of the mother. Trait measures also revealed an association between the maternal grandmother's age and the major autistic trait-the Coherence Scale (regression coefficient b = 0.142, [95%CI = 0.057, 0.228]P = 0.001). After allowing for confounders the effect size increased to b = 0.217[95%CI 0.125, 0.308](P<0.001) for each 10 year increase in age.

Conclusions: Although the relationship between maternal grandmother's age and ASD and a major autistic trait was unexpected, there is some biological plausibility, for the maternal side at least, given that the timing of female meiosis I permits direct effects on the grandchild's genome during the grandmother's pregnancy. An alternative explanation is the meiotic mismatch methylation (3 M) hypothesis, presented here for the first time. Nevertheless the findings should be treated as hypothesis generating pending corroborative results from other studies.

Figure 1. Rates per 1000 of a child having ASD are shown according to ages of parents at child's birth and of grandparents at parents' birth with 95% CIs.

Figure 2. Three generations of genotypes are illustrated (A): that involving the grandmother's pregnancy, her female fetus and the fetal ovary that contains the emerging genotype of the grandchild.

The grandmother has two normal, wild type genes (++). The fetus has a deletion of the gene inherited from grandfather (▵) which confers some susceptibility to autistic spectrum disorder. The hypothesised mispairing of the grandparental chromosomes at the site of the gene deletion (▵) in the fetal oocytes is shown (B). The chromosome containing the wild type gene loops out at meiotic pairing and this gene becomes liable to be silenced by DNA methylation. This results in no grandchild receiving a functional gene.