Genetic relationship between the immune system and autism

Abstract

Autism spectrum disorder (ASD) is a common and complex neurodevelopmental condition. The pathophysiology of ASD is poorly defined; however, it includes a strong genetic component and there is increasing evidence to support a role of immune dysregulation. Nonetheless, it is unclear which immune phenotypes link to ASD through genetics. Hence, we investigated the genetic correlation between ASD and diverse classes of immune conditions and markers; and if these immune-related genetic factors link to specific autistic-like traits in the population. We estimated global and local genetic correlations between ASD (n = 55,420) and 11 immune phenotypes (n = 14,256-755,406) using genome-wide association study summary statistics. Subsequently, polygenic scores (PGS) for these immune phenotypes were calculated in a population-based sample (n = 2487) and associated to five autistic-like traits (i.e., attention to detail, childhood behaviour, imagination, rigidity, social skills), and a total autistic-like traits score. Sex-stratified PGS analyses were also performed. At the genome-wide level, ASD was positively correlated with allergic diseases (ALG), and negatively correlated with lymphocyte count, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) (FDR-p = 0.01-0.02). At the local genetic level, ASD was correlated with RA, C-reactive protein, and granulocytes and lymphocyte counts (p = 5.8 × 10^-6-0.002). In the general population sample, increased genetic liability for SLE, RA, ALG, and lymphocyte levels, captured by PGS, was associated with the total autistic score and with rigidity and childhood behaviour (FDR-p = 0.03). In conclusion, we demonstrated a genetic relationship between ASD and immunity that depends on the type of immune phenotype considered; some increase likelihood whereas others may potentially help build resilience. Also, this relationship may be restricted to specific genetic loci and link to specific autistic dimensions (e.g., rigidity).

Keywords: Autism; Autistic traits; GWAS; Immune; Polygenic risk scores.

Fig. 1

Genetic correlation plot summarising the results of the global genetic correlation analyses between ASD and immune-related phenotypes. Colour bar indicates variation in the strength and direction of genetic correlation estimates (rg) with positive rg in blue and negative rg in red. The FDR-corrected significant correlations are marked with an asterisk (*). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Bar plots for the association between polygenic scores for different immune-related phenotypes and rigidity. Each bar corresponds to the PGS calculated at the GWAS p-value threshold (Pt) listed on the x-axis. The height of the bar (y-axis) represents the degree of variance explained by each PGS in rigidity. The bar colour indicates the significance of the association (according to the -log10(p-value)). The p-value of association for each PGS is reported on the top of each bar. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Bar plot results indicating the variance that polygenic scores for immune phenotypes associated with ASD explain in ‘childhood behaviour’.