Genetic identification of tissues and cell types underlying attention-deficit/hyperactivity disorder

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 non-coding 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 (LDSR) 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 (EWCE) analysis.

Results: By integrating the brain eQTL data and ADHD GWAS data using SMR, we identified 247 genes associated with ADHD. The LDSR 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.

Keywords: ADHD; GWAS; cell type enrichment; gene expression; tissues enrichment.

Figure 1

Manhattan plot of the SMR analysis integrating ADHD GWAS data with the BrainMeta eQTL data. P-value indicates the statistical significance of the SMR analysis results. The dotted line represented the SMR significant threshold (P_SMR < 0.01). For genes with P_SMR < 0.001 and P_HEIDI > 0.01, we also marked the gene names in the figure.

Figure 2

Mapping of SMR risk genes to synaptic locations using SynGO. According to the location of genes in the synapse, genes were divided into presynaptic, postsynaptic, synaptic cleft, synaptic membrane, and extrasynaptic genes. Similar to a directed acyclic graph of GO, terms in the outer ring are a subset of those in the adjacent inner ring.

Figure 3

LDSC-SEG analysis results of ADHD-relevant tissues. Only the top 30 tissues are shown according to the descending order of log₁₀ (p-value).

Figure 4

Associations between ADHD and cell types from the human fetal neocortex using scRNA-seq data from Polioudakis et al. (22) (A) and Trevino et al. (23) (B). Tissues labeled with two asterisks indicate Bonferroni adjusted significance (P < 0.05 for the Polioudakis et al. (22) data; P < 0.05 for the Trevino et al. (24) data). Tissues labeled with one asterisk indicate the nominal significance (P < 0.05). End, endothelial cell; ExDp1, excitatory deep layer 1; ExDp2, excitatory deep layer 2; ExM, maturing excitatory; ExM-U, maturing excitatory upper enriched; ExN, migrating excitatory; InCGE, interneuron; InMGE, interneuron MGE; IP, intermediate progenitor; Mic, microglia; OPC, oligodendrocyte precursors; oRG, outer radial glia; Per, pericyte; PgG2M, cycling progenitors (G2/M phase); PgS, cycling progenitors; vRG, ventricular radial glia; GluN, glutamatergic neuron; SP, subplate; nIPC, neuronal intermediate progenitor cell; lateRG, late radial glia; earlyRG, early radial glia; VLMC, leptomeningeal cells; tRG, truncated radial glia; RBC, red blood cells; Peric, pericytes; OPC_oligo, OPC and oligodendrocyte; mGPC, multipotent glial progenitor; CycProg, cycling progenitors.