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


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Arenella, M, Cadby, G, De Witte, W, Jones, RM, Whitehouse, AJO, Moses, EK ORCID: 0000-0001-7781-4465, Fornito, A, Bellgrove, MA, Hawi, Z, Johnson, B, Tiego, J, Buitelaar, JK, Kiemeney, LA, Poelmans, G and Bralten, J 2021 , 'Potential role for immune-related genes in autism spectrum disorders: Evidence from genome-wide association meta-analysis of autistic traits' , Autism , pp. 1-12 , doi: 10.1177/13623613211019547.

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The clinical heterogeneity of autism spectrum disorders majorly challenges their genetic study. Autism spectrum disorderssymptoms occur in milder forms in the general population, as autistic-like traits, and share genetic factors with autismspectrum disorders. Here, we investigate the genetics of individual autistic-like traits to improve our understanding ofautism spectrum disorders. We meta-analysed four population-based genome-wide association studies investigatingfour autistic-like traits – ‘attention-to-detail’, ‘imagination’, ‘rigidity’ and ‘social-skills’ (n=4600). Using autism spectrumdisorder summary statistics from the Psychiatric Genomic Consortium (N=46,350), we applied polygenic risk scoreanalyses to understand the genetic relationship between autism spectrum disorders and autistic-like traits. UsingMAGMA, 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 variantsand genes, we demonstrated a role of the immune-related genes RNF114, CDKN2A, KAZN, SPATA2 and ZNF816A inautistic-like traits. Brain-based genetic expression analyses further linked autistic-like traits to genes involved in immunefunctioning, 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 insightsshowing a potential role of the immune system in specific autism spectrum disorder dimensions.

Item Type: Article
Authors/Creators:Arenella, M and Cadby, G and De Witte, W and Jones, RM and Whitehouse, AJO and Moses, EK and Fornito, A and Bellgrove, MA and Hawi, Z and Johnson, B and Tiego, J and Buitelaar, JK and Kiemeney, LA and Poelmans, G and Bralten, J
Keywords: autism spectrum disorders, genetics, immune system, molecular and cellular biology
Journal or Publication Title: Autism
Publisher: Sage Publications Ltd.
ISSN: 1362-3613
DOI / ID Number: 10.1177/13623613211019547
Copyright Information:

© The Author(s) 2021. Creative Commons Attribution 4.0 International (CC BY 4.0) License, (

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