Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait

Abstract

Background: Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort.

Methods: We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters.

Results: Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC.

Conclusions: Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.

Keywords: ASD; IQ; autism spectrum disorder; body metrics; genetic ancestry; head circumference.

Figure 1

Plot of head circumference versus age by sex and self-reported ancestry. Plot includes lines for a fitted smooth spline (blue) and the fitted value (red) from the model.

Figure 2

Plots of full-scale IQ versus deviation of head circumference from its expected value based on a genetic model and covariates (genetic deviation). Blue line is the fitted smooth spline; red line is the fitted value from the model with the absolute value of the genetic deviation as the predictor.

Figure 3

Plots of z-score against deviation from expected head circumference in all individuals (grey), in individuals carrying de novo exonic mutations published in O'Roak et al (red) and their siblings (blue).