Multi-tissue transcriptome-wide association study identifies 29 risk genes associated with...

Area of Science:

• Neurogenetics
• Psychiatric Disorders
• Bioinformatics

Background:

• Attention-deficit/hyperactivity disorder (ADHD) is a common, heritable neurodevelopmental disorder affecting millions of children.
• The genetic underpinnings of ADHD remain largely uncharacterized.
• Transcriptome-wide association studies (TWAS) integrate gene expression data with genetic association data to identify risk genes for complex traits.

Purpose of the Study:

• To conduct a multi-tissue TWAS for ADHD to better understand its genetic architecture.
• To identify specific genes whose genetically regulated expression is associated with ADHD risk.
• To discover novel genetic risk factors for ADHD and potential therapeutic targets.

Main Methods:

• Applied the OTTERS TWAS framework using cis-expression quantitative trait loci (eQTL) data from MetaBrain across cortex, basal ganglia, and cerebellum.
• Integrated gene expression data with large-scale ADHD genome-wide association study (GWAS) summary statistics (n=225,534).
• Performed fine-mapping, colocalization, and functional enrichment analyses to prioritize candidate genes and pathways.

Main Results:

• Identified 29 significant TWAS risk genes for ADHD across the three brain tissues.
• Discovered six novel candidate genes (MPL, C1orf210, MDFIC, NKX2-2, FAM183A, HIGD1A) not previously linked to ADHD.
• Found enrichment for neurodevelopmental pathways in cortex and basal ganglia, and a significant protein-protein interaction network.

Conclusions:

• This multi-tissue TWAS successfully refined the genetic architecture of ADHD by implicating specific genes.
• The identification of novel ADHD-associated genes provides new avenues for translational research and drug development.
• Findings contribute to a deeper understanding of the genetic basis of ADHD and related neurodevelopmental conditions.