A genome-wide association study of social and non-social autistic-like traits in the general population using pooled DNA, 500 K SNP microarrays and both community and diagnosed autism replication samples

Abstract

Two separate genome-wide association studies were conducted to identify single nucleotide polymorphisms (SNPs) associated with social and nonsocial autistic-like traits. We predicted that we would find SNPs associated with social and non-social autistic-like traits and that different SNPs would be associated with social and nonsocial. In Stage 1, each study screened for allele frequency differences in approximately 430,000 autosomal SNPs using pooled DNA on microarrays in high-scoring versus low-scoring boys from a general population sample (N = approximately 400/group). In Stage 2, 22 and 20 SNPs in the social and non-social studies, respectively, were tested for QTL association by individually genotyping an independent community sample of 1,400 boys. One SNP (rs11894053) was nominally associated (P < .05, uncorrected for multiple testing) with social autistic-like traits. When the sample was increased by adding females, 2 additional SNPs were nominally significant (P < .05). These 3 SNPs, however, showed no significant association in transmission disequilibrium analyses of diagnosed ASD families.

Fig. 1

Histograms showing the distributions of the social (top figure) and nonsocial (bottom figure) autistic-like trait scales in the male-only unrelated TEDS sample used in Stage 1. Dotted lines indicate the cutoffs employed for selecting the high-scoring and low-scoring groups in each study

Fig. 2

Scatterplot showing allele frequencies (AF) of all SNPs for high versus low social groups from Stage 1. The 23 top-ranked SNPs (crosses) are shown against the background of 433,813 unselected autosomal SNPs comparing AF for the low (x-axis) and high i.e. impaired (y-axis) social groups. The figure also displays the density of SNPs as the density map changes from light (sparse clusters) though to dark (dense clusters). AF differences are small with the majority of differences occurring for SNPs with minor allele frequencies of .10–.25, which reflects the representation of SNPs with these allele frequencies on the Affymetrix microarray. The more extreme deviants (than those selected) failed to meet the 5 selection criteria, as outlined in the “Design and procedures”

Fig. 3

Scatterplot showing allele frequencies (AF) of all SNPs for high versus low nonsocial groups from Stage 1. The 24 top-ranked SNPs (crosses) are shown against the background of 435,457 unselected SNPs comparing AF for the low (x-axis) and the high (y-axis) nonsocial groups. The figure also displays the density of SNPs—see Fig. 1 for further details

Fig. 4

Genotype-by-phenotype plot for rs11894053 (correlated in the male-only sample) illustrating the effect of genotype (x-axis) on standardized social autistic-like trait scores (y-axis)