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

Abstract

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 ≤ 10−5) were also followed up in Autism Genetic Resource Exchange pedigrees (N = 793) and the Autism Case Control cohort (Ncases/Ncontrols = 1,204/6,491).ResultsGCTA 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).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.

Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications

“…ASD-like behaviours have also been exhibited in SH3 and multiple ankyrin repeat domains 3 (SHANK3) mouse models (Peca et al, 2011) with mutations and copy number variations in SHANK3 being strongly associated with ASD (Durand et al, 2007;Sykes et al, 2009) and with SHANK3 interacting directly with mGluR5 through binding of Homer and phospholipase C (PLC) to regulate signalling (Hwang et al, 2005;Tu et al, 1999). In addition, a recent meta-analysis has demonstrated that mutations in SHANK3 are present in 0.69% of patients with ASD, with SHANK1 and 2 mutations to a lesser extent present in 0.04% and 0.17% respectively (Leblond et al, 2014) with SNPs and CNVs in PLCB1 also recently been identified and linked to ASD (Girirajan et al, 2013;St Pourcain et al, 2014). Furthermore, dysregulation in the methylation status of SHANK3 in post-mortem brains of individuals with ASD versus controls has also been demonstrated as well as inhibition of SHANK3 being shown to cause a reduction in synaptic expression of mGluR5 in hippocampal and cortical neuronal cultures, leading to reduced spine density and mini EPSCs (Verpelli et al, 2011).…”

Insights into the Genetic Foundations of Human Communication

“…General cognitive ability is highly heritable, but GWAS studies have struggled to find significant effects for common variants, nor has any association been found with low-frequency CNVs (Davies et al 2011;McRae et al 2013;Kirkpatrick et al 2014). GWAS studies for social behavior have faced similar difficulties (Ebstein et al 2010;St Pourcain et al 2013, 2014b). However, a GWAS for educational attainment in over 100,000 individuals identified three SNPs which reached genome-wide significance, and these associations were replicated in a further sample of 25,000 individuals (Rietveld et al 2013), illustrating that very large sample sizes do have the power to detect small contributions from common SNPs to normal phenotypic variation.…”

Streptococcal infection-related autoimmunity and autism: crosstalk in protein functional networks

“…This data was used in a reconstruction of functional networks linking the antibodies targets to genes relevant to autism (Supplementary table 2). The genes were chosen via GWAS studies by the correlation of relevant SNPs to autistic phenotype (genes) [28][29][30][31].…”