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

Abstract

The clinical heterogeneity of autism spectrum disorders majorly challenges their genetic study. Autism spectrum disorders symptoms occur in milder forms in the general population, as autistic-like traits, and share genetic factors with autism spectrum disorders. Here, we investigate the genetics of individual autistic-like traits to improve our understanding of autism spectrum disorders. We meta-analysed four population-based genome-wide association studies investigating four autistic-like traits – ‘attention-to-detail’, ‘imagination’, ‘rigidity’ and ‘social-skills’ ( n = 4600). Using autism spectrum disorder summary statistics from the Psychiatric Genomic Consortium ( N = 46,350), we applied polygenic risk score analyses to understand the genetic relationship between autism spectrum disorders and autistic-like traits. Using MAGMA, we performed gene-based and gene co-expression network analyses to delineate involved genes and pathways. We identified two novel genome-wide significant loci – rs6125844 and rs3731197 – associated with ‘attention-to-detail’. We demonstrated shared genetic aetiology between autism spectrum disorders and ‘rigidity’. Analysing top variants and genes, we demonstrated a role of the immune-related genes RNF114, CDKN2A, KAZN, SPATA2 and ZNF816A in autistic-like traits. Brain-based genetic expression analyses further linked autistic-like traits to genes involved in immune functioning, and neuronal and synaptic signalling. Overall, our findings highlight the potential of the autistic-like trait–based approach to address the challenges of genetic research in autism spectrum disorders. We provide novel insights showing a potential role of the immune system in specific autism spectrum disorder dimensions. Lay 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.

Updated Research on Autism

“…Data on autism-like traits in four different population cohorts were meta-analyzed and a set of genetic analysis was performed to identify common variants in autismlike traits and to understand how these variants are linked to autism spectrum disorders and how they contribute to neurobiological processes. The findings suggest the genetic relevance of specific autism-like traits and links to the immune system [15].…”

Genetic relationship between the immune system and autism spectrum disorder and traits

“…To assess population structure, multidimensional scaling (MDS) was performed in PLINK (Purcell et al, 2007) and the first four MDS components were retained as covariates in subsequent analyses. In addition, participants were asked to complete a self-report questionnaire on autistic-like traits, developed by qualified clinicians at Radboudumc and previously validated in the Dutch population (Arenella et al, 2022; Bralten et al, 2018). The questionnaire consists of 18-items, rated on a 4-point Likert scale, based on the autism quotient (AQ) questionnaire and the ASD criteria listed in the Diagnostic and Statistical Manual of Mental disorder – 5 th edition.…”

Re-emerging concepts of immune dysregulation in autism spectrum disorders

“…association studies brought new data on autistic-like traits or ASD that were associated with common variation affecting immune pathways (38,39). Dysregulation of both the innate and adaptive immune responses appear to be involved in ASD (40)(41)(42).…”

“…These miRNAs target ASD genes and regulate, in correlation with transcription factors, complex metabolic and immune components ( 37 ). Additionally, genome-wide association studies brought new data on autistic-like traits or ASD that were associated with common variation affecting immune pathways ( 38 , 39 ).…”