Genetic investigation of quantitative traits related to autism: use of multivariate polygenic models with ascertainment adjustment

Abstract

Autism is a severe developmental disorder of unknown etiology but with evidence for genetic influences. Here, we provide evidence for a genetic basis of several quantitative traits that are related to autism. These traits, from the Broader Phenotype Autism Symptom Scale (BPASS), were measured in nuclear families, each ascertained through two probands affected by autism spectrum disorder. The BPASS traits capture the continuum of severity of impairments and may be more informative for genetic studies than are the discrete diagnoses of autism that have been used by others. Using a sample of 201 nuclear families consisting of a total of 694 individuals, we implemented multivariate polygenic models with ascertainment adjustment to estimate heritabilities and genetic and environmental correlations between these traits. Our ascertainment adjustment uses conditioning on the phenotypes of probands, requires no modeling of the ascertainment process, and is applicable to multiplex ascertainment and multivariate traits. This appears to be the first such implementation for multivariate quantitative traits. The marked difference between heritability estimates of the trait for language onset with and without an ascertainment adjustment (0.08 and 0.22, respectively) shows that conclusions are sensitive to whether or not an ascertainment adjustment is used. Among the five BPASS traits that were analyzed, the traits for social motivation and range of interest/flexibility show the highest heritability (0.19 and 0.16, respectively) and also have the highest genetic correlation (0.92). This finding suggests a shared genetic basis of these two traits and that they may be most promising for future gene mapping and for extending pedigrees by phenotyping additional relatives.

Figure 1

Covariate effects (age and sex) for social motivation when estimates with ascertainment adjustment are used. Solid and dashed lines represent males and females, respectively. The vertical dotted line indicates age 18 years.

Figure 2

Box plots for IQ and age-and-sex–adjusted BPASS traits. A = 297 affected children; U = 54 unaffected children; P = 343 parents. Each box shows lower quartile, median, and upper quartile. The whiskers extend to the most extreme data point that is no more than 1.5 times the interquartile range from the box.