title: Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence.
abstract: BACKGROUND
  Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence.
  
  
  METHODS
  Social-communication difficulties were ascertained at ages 8, 11, 14 and 17 years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N ≤ 5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P ≤ 10-5) were also followed up in Autism Genetic Resource Exchange pedigrees (N = 793) and the Autism Case Control cohort (Ncases/Ncontrols = 1,204/6,491).
  
  
  RESULTS
  GCTA heritability was strongest in childhood (h2(8 years) = 0.24) and especially in later adolescence (h2(17 years) = 0.45), with a marked drop during early to middle adolescence (h2(11 years) = 0.16 and h2(14 years) = 0.08). Genome-wide screens at ages 8 and 17 years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P = 9.3 × 10-9; genome-wide empirical P = 0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P = 7.9 × 10-8; genome-wide empirical P = 0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location = 0.007).
  
  
  CONCLUSIONS
  Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum.
authors.affiliation: The Medical Research Council Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. Beate.StPourcain@bristol.ac.uk.
authors.forename: Beate
authors.initials: B
authors.lastname: St Pourcain
authors.forename: David H
authors.initials: DH
authors.lastname: Skuse
authors.forename: William P
authors.initials: WP
authors.lastname: Mandy
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.forename: Wendy L
authors.initials: WL
authors.lastname: McArdle
authors.forename: Jean
authors.initials: J
authors.lastname: Golding
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith