Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence.

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TitleVariability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence.
Publication TypeJournal Article
Year of Publication2014
AuthorsSt Pourcain, B, Skuse, DH, Mandy, WP, Wang, K, Hakonarson, H, Timpson, NJ, Evans, DM, Kemp, JP, Ring, SM, McArdle, WL, Golding, J, Smith, GDavey
JournalMol Autism
Date Published2014 Feb 24

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.

Alternate JournalMol Autism
PubMed ID24564958
PubMed Central IDPMC3940728
Grant ListG0400085 / / Medical Research Council / United Kingdom
MC_UU_12013/3 / / Medical Research Council / United Kingdom
092731 / / Wellcome Trust / United Kingdom
102215 / / Wellcome Trust / United Kingdom
MC_PC_15018 / / Medical Research Council / United Kingdom
MC_UU_12013/1 / / Medical Research Council / United Kingdom
MC_UU_12013/4 / / Medical Research Council / United Kingdom
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