title: 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.
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; FondaMental Foundation, Créteil, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Chaste
authors.forename: Lambertus
authors.initials: L
authors.lastname: Klei
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.forename: Michael T
authors.initials: MT
authors.lastname: Murtha
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hus
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lowe
authors.forename: A Jeremy
authors.initials: AJ
authors.lastname: Willsey
authors.forename: Daniel
authors.initials: D
authors.lastname: Moreno-De-Luca
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Yu
authors.forename: Eric
authors.initials: E
authors.lastname: Fombonne
authors.forename: Daniel
authors.initials: D
authors.lastname: Geschwind
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Grice
authors.forename: David H
authors.initials: DH
authors.lastname: Ledbetter
authors.forename: Catherine
authors.initials: C
authors.lastname: Lord
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.forename: Christa
authors.initials: C
authors.lastname: Lese Martin
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
authors.forename: Eric M
authors.initials: EM
authors.lastname: Morrow
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Soo-Jeong
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000328:Adult; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D001837:Body Weights and Measures; D002648:Child; D005190:Family; D005260:Female; D006257:Head / Q000473:pathology*; D006801:Humans; D007360:Intelligence / Q000502:physiology; D008297:Male; D019655:Quantitative Trait, Heritable
keywords: ASD; IQ; autism spectrum disorder; body metrics; genetic ancestry; head circumference