AUTHOR=Wei Wen-Qiong , Sun Hong , Chen Ya-Juan , Liu Xiao-Wen , Zhou Rui , Li Yi , Liu Xin-Wen TITLE=Genetic identification of tissues and cell types underlying attention-deficit/hyperactivity disorder JOURNAL=Frontiers in Psychiatry VOLUME=Volume 13 - 2022 YEAR=2022 URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.999007 DOI=10.3389/fpsyt.2022.999007 ISSN=1664-0640 ABSTRACT=Background: Genome-wide association studies (GWASs) have identified numerous genetic variants associated with attention-deficit/hyperactivity disorder (ADHD), which is considered highly genetically heritable. However, because most of the variants located in the noncoding region of the human genome, the onset of ADHD requires further exploration. Methods: The risk genes involved in ADHD were identified by integrating GWAS summary data and expression quantitative trait locus (eQTL) data using summary data-based Mendelian randomization (SMR) method. We then used a stratified linkage disequilibrium score regression method to estimate the contribution of ADHD-relevant tissues to its heritability to screen out disease-relevant tissues. To determine the ADHD-relevant cell types, we used an R package for expression-weighted cell type enrichment analysis. Results: By integrating the brain eQTL data and ADHD GWAS data using SMR, we identified 247 genes associated with ADHD. The linkage disequilibrium score regression applied to specifically expressed genes results showed that the ADHD risk genes were mainly enriched in brain tissue, especially in the mesencephalon, visual cortex, and frontal lobe regions. Further cell-type-specific analysis suggested that ADHD risk genes were highly expressed in excitatory neurons. Conclusion: The study showed that the etiology of ADHD is associated with excitatory neurons in the midbrain, visual cortex, and frontal lobe regions.