title: Combined genome-wide linkage and targeted association analysis of head circumference in autism spectrum disorder families.
abstract: BACKGROUND
  It has long been recognized that there is an association between enlarged head circumference (HC) and autism spectrum disorder (ASD), but the genetics of HC in ASD is not well understood. In order to investigate the genetic underpinning of HC in ASD, we undertook a genome-wide linkage study of HC followed by linkage signal targeted association among a sample of 67 extended pedigrees with ASD.
  
  
  METHODS
  HC measurements on members of 67 multiplex ASD extended pedigrees were used as a quantitative trait in a genome-wide linkage analysis. The Illumina 6K SNP linkage panel was used, and analyses were carried out using the SOLAR implemented variance components model. Loci identified in this way formed the target for subsequent association analysis using the Illumina OmniExpress chip and imputed genotypes. A modification of the qTDT was used as implemented in SOLAR.
  
  
  RESULTS
  We identified a linkage signal spanning 6p21.31 to 6p22.2 (maximum LOD = 3.4). Although targeted association did not find evidence of association with any SNP overall, in one family with the strongest evidence of linkage, there was evidence for association (rs17586672,p= 1.72E-07).
  
  
  CONCLUSIONS
  Although this region does not overlap with ASD linkage signals in these same samples, it has been associated with other psychiatric risk, including ADHD, developmental dyslexia, schizophrenia, specific language impairment, and juvenile bipolar disorder. The genome-wide significant linkage signal represents the first reported observation of a potential quantitative trait locus for HC in ASD and may be relevant in the context of complex multivariate risk likely leading to ASD.
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON Canada.|Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON Canada.|St Joseph's Healthcare, West 5th Campus, 100 West 5th Street, Hamilton, ON Canada.
authors.forename: M
authors.identifier: 0000-0002-0593-8917
authors.initials: M
authors.lastname: Woodbury-Smith
authors.affiliation: Department of Psychiatry, University of Utah, Salt Lake City, UT USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Bilder
authors.affiliation: Department of Psychiatry, University of Utah, Salt Lake City, UT USA.
authors.forename: J
authors.initials: J
authors.lastname: Morgan
authors.affiliation: Department of Psychiatry, University of Utah, Salt Lake City, UT USA.
authors.forename: L
authors.initials: L
authors.lastname: Jerominski
authors.affiliation: Department of Psychiatry, University of Utah, Salt Lake City, UT USA.
authors.forename: T
authors.initials: T
authors.lastname: Darlington
authors.affiliation: University of Texas Rio Grande Valley School of Medicine and South Texas Diabetes and Obesity Institute, Harlingen, TX USA.
authors.forename: T
authors.initials: T
authors.lastname: Dyer
authors.affiliation: Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON Canada.|Division of Epidemiology and Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON Canada.
authors.forename: A D
authors.initials: AD
authors.lastname: Paterson
authors.affiliation: Department of Psychiatry, University of Utah, Salt Lake City, UT USA.
authors.forename: H
authors.initials: H
authors.lastname: Coon
keywords: Autism spectrum disorder (ASD); Genetic association; Genome-wide linkage; Head circumference (HC)