Quantitative Autistic Traits Index Silently Transmitted ASD Risk across Generations

Background: Multiple previous studies have demonstrated familial aggregation of quantitative autistic traits (QATs) in siblings and parents of individuals with ASD (Constantino et al, 2010, Lyall et al., 2014; Page et al., 2016).

Objectives: Here, we build upon the existing knowledge base via two new transgenerational studies examining the extent to which inherited behavioral phenotypes index causal influence for ASD.

Methods: The first transgenerational sample was comprised of epidemiologically-ascertained toddler twins and their parents. Measurement of QATs of parents and their children was implemented using the Social Responsiveness Scale-2 (SRS). Additionally, the toddlers were behaviorally phenotyped using eye-tracking measures of social visual engagement (SVE), which exhibit extremely high heritability and are strongly associated with the development of clinical autistic syndromes (Constantino et al., Nature 2017). In the second study, data from 150 multiplex ASD families enrolled in prior research were reviewed for transmission patterns strongly suspicious for silent maternal transmission of genetic risk, which is a putative mechanism for the so-called “female protective effect.”

Results: Analyses in toddlers demonstrated that the biparental mean for QATs indexed by parental SRS scores predicted the SRS scores of their children at 36 months (r=.355, p<.001, n=142); heritability of the latter estimated from twin data was on the order of 0.85. Notably, QATs and SVE scores, based on total fixation time for looking at eyes, were uncorrelated (r=.037, p=.746) and equally heritable, indicating that SVE measurements constitute a separate quantitative behavioral phenotype indexing genetic risk for ASD.

In the second study, 15 of 150 multiplex families manifested an intergenerational transmission pattern in which all affected individuals were males and each mother of a son with ASD also had a male first degree relative (in her own generation or the preceding generation; i.e. among her brothers or father). Average SRS T-scores of such “suspected-silent-transmitter” mothers were 11 points greater than mothers in multiplex ASD families who did not fit this pattern of transmission, indicating a higher burden of autistic traits (t(9.3)=2.67, p=.025, effect size=.47) and corresponding to a raw SRS score 12 points greater than the general population mean. We note also that in an evolving prospective collection of second generation offspring of the sisters of males with ASD (who have previously been shown to manifest aggregations of sub clinical autistic traits), we have observed a rate of confirmed and suspected ASD in their male offspring of 24% in comparison to a rate of 10% in female offspring.

Conclusions: These data significantly expand upon the accumulated knowledge base on quantitative behaviors traits that index causal liability for ASD, and that might ultimately be utilized to identify females of childbearing age—particularly those in ASD-affected families—who are at elevated risk for silent transmission of ASD risk to their offspring.