Age at First Birth Has Genetic Determinants and Is Related to Social Responsiveness

Background: The age at which parents of both sexes have children has been associated with increased risk of autism spectrum disorders (ASDs). Though the reasons for this are unknown, they are often hypothesized to be due to chromosomal changes in eggs and de novo mutations in sperm. An alternative mechanism has been speculated that subclinical ASD-like behaviors lead to delayed childbearing. Social aptitude (measured as Social Responsiveness Scale score, SRS) is heritable and closely related to ASDs. It has been observed that, on average, parents of children with ASDs have lower social responsiveness. This leads to a hypothesis that the age a parent has a first child (age at first birth, ageFB) is not a causal risk factor for ASDs, but instead, parental social responsiveness may influence ageFB and ASD risk separately. As SRS is highly heritable, these effects are likely mediated by genetics.

Objectives: The study aimed to clarify the nature of the relationship between ageFB and ASD risk. We used genome-wide genetic data from several ASD datasets to measure the heritability of ageFB and assess the relationship between ageFB and SRS. These data were additionally used to identify common variants associated with both traits.

Methods:  In order to estimate the genetic component of ageFB, the heritability of the trait was measured in the Early Markers for Autism (EMA, N=333 primiparous mothers of cases and controls) dataset and Simons Simplex Collection (SSC, N=1,580 trio parents) dataset. Correlation between ageFB and SRS, as well as a GWAS of SRS, were performed in the SSC for both parents. A GWAS of ageFB was performed as a meta-analysis across the EMA, SSC, and part of the Autism Genetic Resource Exchange (AGRE) datasets (N=3,855).

Results:  In SSC parents, adjusting for genetic ancestry, sex, and educational attainment, ageFB was found to be significantly heritable (P<5.8x10^-4). Correlation between ageFB and parental SRS in SSC was significant in a similarly adjusted model (P<2.2x10^-16). The top ageFB locus (P=9.1x10^-11) fell near the ASTN2 gene, close to an ASD candidate gene identified by the Psychiatric Genomics Consortium (PGC) and implicated previously in ASDs based on analysis of rare variants. The ageFB loci identified in ASD parents show several overlapping loci with published population-based ageFB studies. Further, one of the top loci associated with SRS in ASD parents was a population ageFB locus, suggesting the relationship between social aptitude and ageFB is likely to generalize beyond ASD families.

Conclusions: This study of parents of children with ASDs finds that ageFB appears heritable and correlated with SRS. Furthermore, both traits have associated genetic variants, with overlap between loci associated with ageFB, SRS, and ASDs. The relationship between ageFB and SRS supports a hypothesis that the link between parental age and ASD risk in offspring is mediated through the genetics of social responsiveness. Because the parental behaviors leading to delayed childbearing are heritable, these traits may present themselves as ASDs in offspring. The information gained from our study can help parents make informed decisions.