Genetic investigation of quantitative traits related to autism: use of multivariate polygenic models with ascertainment adjustment.
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.
Sung
Yun Ju
YJ
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195-7720, USA.
Dawson
Geraldine
G
Munson
Jeffrey
J
Estes
Annette
A
Schellenberg
Gerard D
GD
Wijsman
Ellen M
EM
D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007361:Intelligence Tests; D008297:Male; D008957:Models, Genetic; D015233:Models, Statistical; D005810:Multigene Family; D019655:Quantitative Trait, Heritable; D012917:Social Adjustment