Adjusting Head Circumference for Covariates in Autism: Clinical Correlates of a Highly Heritable Continuous Trait

• Type of Material: Article
• Authors: Pauline Chaste, University of Pittsburgh; Lambertus Klei, University of Pittsburgh; Stephan J Sanders, Yale University; Michael T Murtha, Yale University; Vanessa Hus, University of Michigan; Jennifer K Lowe, University of California Los Angeles; A Jeremy Willsey, Yale University; Daniel Moreno-De-Luca, Yale University; Timothy W Yu, Harvard University; Christa Martin, Emory University
• Language: English
• Date: 2013-10-15
• Publisher: Elsevier Science INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Society of Biological Psychiatry.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2013.04.018
• Title of Journal or Parent Work: Biological Psychiatry
• Volume: 74
• Issue: 8
• Start Page: 576
• End Page: 584
• Grant/Funding Information: This work was supported by a grant from the Simons Foundation (SFARI 124827 to the investigators of the SSC Genetic Consortium); NIH K23MH082883 (SJK); NIH R01HD065272 (CL); NIH R01MH089390 (CL) and Fondamental Foundation (PC).
• Keywords: ENLARGEMENT; Neurosciences & Neurology; head circumference; genetic ancestry; autism spectrum disorder; body metrics; BIRTH; DISORDER; LIFE; BRAIN VOLUME; CHILDREN; 1ST YEAR; Neurosciences; SIZE; AGE; Life Sciences & Biomedicine; Science & Technology; GROWTH; Psychiatry; ASD; IQ
• Research Categories: Biology, Neuroscience; Health Sciences, Medicine and Surgery

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.