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