Potential role for immune-related genes in autism spectrum disorders: Evidence from genome-wide association meta-analysis of autistic traits

Abstract

Autism spectrum disorders are complex, with a strong genetic basis. Genetic research in autism spectrum disorders is limited by the fact that these disorders are largely heterogeneous so that patients are variable in their clinical presentations. To address this limitation, we investigated the genetics of individual dimensions of the autism spectrum disorder phenotypes, or autistic-like traits. These autistic-like traits are continuous variations in autistic behaviours that occur in the general population. Therefore, we meta-analysed data from four different population cohorts in which autistic-like traits were measured. We performed a set of genetic analyses to identify common variants for autistic-like traits, understand how these variants related to autism spectrum disorders, and how they contribute to neurobiological processes. Our results showed genetic associations with specific autistic-like traits and a link to the immune system. We offer an example of the potential to use a dimensional approach when dealing with heterogeneous, complex disorder like autism spectrum disorder. Decomposing the complex autism spectrum disorder phenotype in its core features can inform on the specific biology of these features which is likely to account to clinical variability in patients.

Keywords: autism spectrum disorders; genetics; immune system; molecular and cellular biology.

Figure 1.

Manhattan plot of the GWAS meta-analysis for ‘attention to detail’. Each dot represents the result of the linear regression analysis for each single variant taking the attention to detail mean score as dependent variable and correcting for age, sex, gender and four MDS components. The x-axis shows the chromosomes and the y-axis shows the −log (two-sided) p-value of the association. The red dotted line indicates the threshold for genome-wide significance.

Figure 2.

Polygenic risk-based results of ASDs and ‘rigidity’. Polygenic risk score-based results showing the degree of shared genetic aetiology between ASDs (‘base’ phenotype) and ‘rigidity’ (‘target’ phenotype) at seven broad p-value thresholds (P_T). The bar plot was created with PRSice1. The x-axis displays the seven p-value thresholds tested and the y-axis displays the variance explained by the genetics of the ‘base’ phenotype in the ‘target’ phenotype. The colours of the bars indicated the −log10 p-value of the association. *p-values < 0.05 after FDR-correction; **p-values < 0.01 after FDR-correction.

Figure 3.

Summary figure of immune-related findings in ALT genetics. Summary figure to illustrate our findings pointing to a relationship between ALTs and the immune system. On the right, results of gene-wide analyses highlight significant ALTs associations with genes that are involved in immune functioning (NF-KB signalling). On the left, results of gene co-expression network analyses show that eQTL-genes, linked to ALTs, for total cortex, putamen and nucleus accumbens are enriched in immune processes (association p-values for the immune pathways are reported). *Genes exceeded the Bonferroni-corrected p-value threshold of 2.8e−6.