Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescenceReport as inadecuate

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Molecular Autism

, 5:18

First Online: 24 February 2014Received: 04 November 2013Accepted: 04 February 2014


BackgroundSocial-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.

MethodsSocial-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 were also followed up in Autism Genetic Resource Exchange pedigrees N = 793 and the Autism Case Control cohort Ncases-Ncontrols = 1,204-6,491.

ResultsGCTA heritability was strongest in childhood h8 years = 0.24 and especially in later adolescence h17 years = 0.45, with a marked drop during early to middle adolescence h11 years = 0.16 and h14 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; genome-wide empirical P = 0.011 and suggestive evidence at 20p12.3 at PLCB1 rs3761168, P = 7.9 × 10; 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.

ConclusionsOur 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.

KeywordsALSPAC ASD Autism GCTA heritability GWAS Social communication AbbreviationsASDAutism spectrum disorder

ADI–RAutism Diagnostic Interview–Revised

ACCAutism Case Control cohort

AGREAutism Genetic Resource Exchange

ALSPACAvon Longitudinal Study of Parents and Children

GCGenomic control

GCTAGenome-wide Complex Trait Analysis

GWASGenome-wide association study

HapMapCEUUtah residents with Northern and Western European ancestry from the Centre d’Etude du Polymorphisme Humain collection

LCLLymphoblastoid cell line

LDLinkage disequilibrium

LDLRLow-density lipoprotein receptor

MAFMinor allele frequency

MDSMultidimensional scaling

QTLQuantitative trait locus

SCDCSocial Communication Disorder Checklist

SNPSingle-nucleotide polymorphism.

Electronic supplementary materialThe online version of this article doi:10.1186-2040-2392-5-18 contains supplementary material, which is available to authorized users.

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Author: Beate St Pourcain - David H Skuse - William P Mandy - Kai Wang - Hakon Hakonarson - Nicholas J Timpson - David M Evans


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