Convergence and divergence of genes informed by common and rare variants of autism spectrum disorders in tissue-specific pathways and gene networks

TL;DR

This study explores how both common and rare genetic variants contribute to autism spectrum disorder by analyzing gene networks in brain and peripheral tissues.

Contribution

The study integrates multi-tissue and multi-omics data to reveal shared and distinct genetic mechanisms of ASD informed by common and rare variants.

Findings

Brain regions involved in synaptic signaling and neurodevelopment are enriched for both common and rare ASD variants.

Peripheral tissues like the digestive and immune systems are primarily influenced by common ASD variants.

Key regulators like SYT1 and ADD2 may coordinate effects of both variant types in ASD pathogenesis.

Abstract

The genetic heterogeneity of autism spectrum disorder (ASD) presents significant challenges in understanding its pathogenic mechanisms, as the genetic risk involves numerous common variants and rare de novo or inherited variants. Prior research has mainly focused on identifying rare variants and their impact on neurodevelopment and neuronal functions in cortical brain regions. By contrast, common variants, which contribute substantially to ASD heritability, remain understudied, suggesting a need to consider both variant types to understand ASD’s genetic mechanisms. Previous studies have also implicated subcortical brain regions and peripheral digestive and immune systems, but tissue-specific mechanisms remain unclear. We address these knowledge gaps by identifying gene networks, pathways, and key regulators informed by ASD common variants in brain and peripheral tissues, further examining whether these networks also capture genes informed by rare variants. Our approach integrates genome wide association study (GWAS) summary statistics, tissue-level genetics of gene expression, and gene coexpression and transcriptional regulatory networks across ~50 tissues. Our multitissue, multiomics analysis reveals that key brain regions and networks crucial for synaptic signaling and neurodevelopment are enriched for both rare and common variants, whereas peripheral tissues, such as the digestive and immune systems, are primarily informed by common variants. This partitioning of key tissues and biological pathways into core (targeted by both variant types) and modifying components provide insight into ASD heterogeneity. We also identified central gene network regulators, such as SYT1 and ADD2, which may orchestrate the effects of both common and rare ASD genetic risk factors on ASD pathogenesis.

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