Common variation contributes to the genetic architecture of social communication traits.

Beate St Pourcain,Wei Q Ang,Hakon Hakonarson,Jean Golding,Susan M Ring,Nicholas J Timpson,Andrewj O Whitehouse,Joseph T Glessner,Craig E Pennell,Kai Wang,John P Kemp,David M Evans,Nicole M Warrington,Wendy L Mcardle,George Davey Smith

doi:10.1186/2040-2392-4-34

Abstract

BackgroundSocial communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype.MethodsWe performed a genome-wide association study on parent-reported social communication problems using items of the children’s communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364).ResultsTwo of our seven independent top signals (P-discovery <1.0E-05) were replicated (0.009 <P-replication ≤0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region.Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027).ConclusionOverall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes.

Highlights

Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development
genome-wide association studies (GWAS) in the ALSPAC cohort revealed an excess of association signals beyond chance while detecting little evidence for population stratification
Selecting the strongest signals from recent Autism spectrum disorders (ASD) GWAS, we investigated whether the allele conferring risk to ASD increased the expression of social communication difficulties in the general population, as captured by the SPC score within the ALSPAC sample

Summary

Introduction

Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. Autism spectrum disorders (ASDs) demarcate the extreme end of a continuum of behavioural difficulties [1], characterised by impairments of social interaction and communication as well as highly restricted interests and/ or stereotyped repetitive behaviours [2]. It is possible that some variants influencing the expression of autistic traits might represent underlying ASD quantitative trait loci (QTL). This assumption is supported by studies showing that common genetic variation at 5p14 [12] carries risk for ASD but is associated with the expression of social communication spectrum phenotypes in the general population [13]. Suggested that there is heterogeneity among the three components of the autistic triad, and that social communication spectrum phenotypes, which are heritable traits [6,15], are potentially aetiologically distinct from other autistic behavioural domains [15,16]

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Conclusion