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.

Figure 1

Genetic and environmental-residual correlations between social-communication problems during development. Lower triangle: genetic correlations (r_g). Upper triangle: environmental-residual correlations (r_e). All correlations are given with their SE.

Figure 2

Association signal at 3p22.2 for social-communication problems at 17 years of age. (a) Chromosome ideogram for chromosome 3. (b) Regional association plot for rs4453791. Directly genotyped and imputed variants are depicted by filled circles according to their genome-wide -log₁₀P-value and their genomic position in megabases (Mb) (build 36). Recombination rates are shown in blue (HapMapCEU, release 22) and the linkage disequilibrium (LD) (r²) between the lead variant and surrounding markers is indicated by the colour code. (c) Detailed genomic region near rs4453791 depicting variants in LD (r² > 0.3), non-coding functional variation (ENCODE (Encyclopedia of DNA Elements) functionality score ≤2; RegulomeDB: http://regulome.stanford.edu/) and a rare autism related de novo single-nucleotide variant (V483M) within XIRP1, a locus with weak candidacy [44]. The LD (r²) between the lead variant and surrounding SNPs is indicated by the shade of grey (0 (white) to 1 (black)).

Figure 3

Association signal at 20p12.3 for social-communication problems at 17 years of age. (a) Chromosome ideogram for chromosome 20. (b) Regional association plot for rs3761168. Directly genotyped and imputed variants are depicted by filled circles according to their genome-wide -log₁₀P-value and their genomic position in megabases (Mb) (build 36). Recombination rates are shown in blue (HapMapCEU, release 22), and the linkage disequilibrium (LD) (r²) between the lead variant and surrounding markers is indicated by the colour code. (c) Detailed genomic region near rs3761168 depicting variants in LD (r² > 0.3) and rare autism related mutations (≥480 kb) within PLCB1. Mutations were either (i) identified in affected family members only [45] or (ii) enriched within patients compared with controls [46] (del, deletions; dup, duplications). The LD (r²) between the lead variant and surrounding SNPs is indicated by the shade of grey (0 (white) to 1 (black)).