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. 2013 Sep 18;4(1):34.
doi: 10.1186/2040-2392-4-34.

Common variation contributes to the genetic architecture of social communication traits

Beate St Pourcain  1 , Andrew J O Whitehouse, Wei Q Ang, Nicole M Warrington, Joseph T Glessner, Kai Wang, Nicholas J Timpson, David M Evans, John P Kemp, Susan M Ring, Wendy L McArdle, Jean Golding, Hakon Hakonarson, Craig E Pennell, George Davey Smith
Affiliations

Common variation contributes to the genetic architecture of social communication traits

Beate St Pourcain et al. Mol Autism. .

Abstract

Background: Social 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.

Methods: We 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).

Results: Two 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).

Conclusion: Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes.

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Figures

Figure 1
Figure 1
Quantile-quantile plot for the genome-wide analysis of social communication difficulties in ALSPAC. The plot is based on genomic-control corrected P-values. Black circles depict the observed association signals, the white diagonal line represents the distribution of signals under the null hypothesis and the shaded area corresponds to the 95% confidence interval. A deviation of the observed from the expected distribution of signals is visible. λ, Genomic-control factor.
Figure 2
Figure 2
Association plot for the association between social communication problems and common variation at 6p22.1. a). Chromosome ideogram for chromosome 6. b). Regional association plot for rs9257616 on chromosome 6p22.1. Directly genotyped and imputed variants are depicted by filled circles according to their GWAS P-value (−log10 P-value) and genomic position (NCBI Build 36). The local LD structure is reflected by HapMap CEU (Rel 22) recombination rates (blue line). The LD (r2) between the lead variant and surrounding SNPs is indicated by the colour code. c). Detailed genomic region near rs9257616 on chromosome 6p22.1 with variants in LD (r2 >0.3) including non-coding functional (Regulome score ≤2) and missense variation. The LD (r2) between the lead variant and surrounding SNPs is indicated by the colour code (0 (white)-1(black)). The local LD structure is reflected by HapMap CEU (Rel 22) r2 –based haplotype blocks. GWAS, genome-wide association studies; LD, linkage disequilibrium; SNPs, single nucleotide polymorphisms.
Figure 3
Figure 3
Association plot for the association between social communication problems and common variation at 14q22.1. a). Chromosome ideogram for chromosome 14. b). Regional association plot for rs2352908 on chromosome 14q22.1. Directly genotyped and imputed variants are depicted by filled circles according to their GWAS P-value (−log10 P-value) and genomic position (NCBI Build 36). The local LD structure is reflected by HapMap CEU (Rel 22) recombination rates (blue line). The LD (r2) between the lead variant and surrounding SNPs is indicated by the colour code. c). Detailed genomic region near rs2352908 on chromosome 14q22.1 with variants in LD (r2 >0.3) including non-coding functional variation (Regulome score ≤2). The LD (r2) between the lead variant and surrounding SNPs is indicated by the colour code (0 (white)-1(black)). The local LD structure is reflected by HapMap CEU (Rel 22) r2 –based haplotype blocks. GWAS, genome-wide association studies; LD, linkage disequilibrium; SNPs, single nucleotide polymorphisms.
Figure 4
Figure 4
Estimate of the proportion of genetic variance in social communication difficulties explained by each chromosome. Numbers reflect individual chromosomes; the blue line indicates the linear regression of chromosome length on the proportion of variation explained (adjusted regression R2 = 0.12, P = 0.06); confidence intervals are indicated in grey.
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