An integrative analysis of transcriptome-wide association study and mRNA expression profile identified candidate genes for attention-deficit/hyperactivity disorder

Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, but the genetic mechanism of ADHD remains elusive now.

Methods: Tissue specific transcriptome-wide association study (TWAS) of ADHD was performed by FUSION utilizing a genome-wide association study (GWAS) dataset of ADHD (including 20,183 ADHD cases and 35,191 healthy controls) and gene expression reference from brain and blood. Furthermore, the genes identified by TWAS were compared with the differently expressed genes detected by mRNA expression profiles of ADHD rat model and autism spectrum disorders (ASD) patients. Functional enrichment and annotation analysis of the identified genes were performed by DAVID and FUMAGWAS tool.

Results: For brain tissue, TWAS identified 148 genes with P value < 0.05, such as TDO2 (P_TWAS=4.01×10^-2), CHD1L (P_TWAS=9.64×10^-3) and KIAA0319L (P_TWAS=4.05×10^-4). Further 11 common genes were examined in the mRNA expression datasets, such as ACSM5 (P_TWAS=3.62×10^-2, P_mRNA=0.005), CCDC24 (P_TWAS=1.49×10^-2, P_mRNA=2.35×10^-3) and MVP (P_TWAS=5.55×10^-3, P_mRNA=5.40×10^-3). Pathway enrichment analysis of the genes identified by TWAS detected 3 pathways for ADHD, including Other glycan degradation (P value=0.021), Viral myocarditis (P value=0.034) and Endocytosis (P value=0.041).

Conclusions: Through integrating GWAS and mRNA expression data, we identified a group of ADHD-associated genes and pathways, providing novel clues for understanding the genetic mechanism of ADHD.

Keywords: Attention-deficit/hyperactivity disorder (ADHD); Gene ontology (GO); Genome-wide association study (GWAS); Pathway; Transcriptome-wide association study (TWAS).