Transgenerational Effects and Heritability of Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) affects an estimated prevalence of 1 in 36 children but the cause in most cases is unknown. Human and animal studies have linked ASD to Folate Receptor Alpha Autoantibodies (FRAAs). Our previous studies demonstrated that FRAAs are more common, on average, in families with children with ASD. This study reanalyzed data from this previous study which included 82 children diagnosed with ASD, 53 unaffected siblings, 70 mothers and 65 fathers and 52 typically developing controls who did not have a history of ASD in their family. This study investigates the association of FRAA titers with ASD risk factors and explores the relationship of FRAA titers across generations. Several known risk factors for ASD, including multiplex ASD families, multiple birth pregnancies and increased maternal and paternal age at birth were related to offspring FRAA titers. Multiplex ASD families demonstrated higher FRAA titers and a significant correlation between maternal and offspring blocking FRAA titers. FRAA titers increased across generations, although the increase in blocking FRAAs was only seen in multiplex families. The proband with ASD demonstrated higher blocking but not binding titers compared to their non-affected siblings. Paternal FRAA titers are associated with several measures of offspring behavior and cognitive development. This research highlights the potential transgenerational transmission of FRAAs and their role in ASD, demonstrating that heritable non-genetic factors may be important in the etiology of ASD and that FRAAs may demonstrate anticipation (worsening across generations), especially in multiplex families. Disruption of immune regulation and susceptibility to autoimmune disease may underly disruption of brain development and function in ASD.