Neurodevelopmental Disorders

Non-Coding Structural Variants for Attention -Deficit Hyperactivity Disorder Linked to Ancestry

Jessica Nye
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While previous studies suggest that structural variants (SVs) play an important role in the development and progression of ADHD, these studies focused mostly on those of European ancestry and coding regions. This particular study seeks to address the role of SVs in non-European populations and outside of coding regions.

Ancestry-linked non-coding structural variants (SVs) were found to play an important role for attention-deficit hyperactivity disorder (ADHD). These results were published in Scientific Reports.

Whole genome sequencing of 875 individuals was performed to identify SVs, including copy number variation, insertions, deletions, inversions, and translocations. Genetic samples were collected from individuals with (n=205) and without (n=670) ADHD. Among donors with and without ADHD, 116 and 408 were Black and 89 and 262 were White, respectively.

Among those with ADHD, 160,000 SVs were identified (56.13% intergenic, 42.3% intronic, 0.96% exonic, and 0.59% splicing).

Although no previously associated exonic variants were replicated during this study, of the SVs likely to alter coding regions (ie, exonic or splicing) 37 were significant for ADHD. For example, a novel deletion of an exon (P =.0083) in IQ Motif and Sec7 Domain 3 (IQSEC3) was identified. This gene is a neuronal exchange gene which has been related to speech and is down-regulated among individuals with schizophrenia and autism.

Among individuals with ADHD, 451 and 382 were found to be significantly associated among Black and White individuals, respectively. The majority of these SVs were located outside coding regions.

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Four SVs identified within non-coding regions of genes in the neuroactive ligand-receptor interaction pathway were identified as significantly enriched among individuals with ADHD. Specifically, an intronic deletion of 5-Hydroxytryptamine Receptor 1F (HTR1F; P =.044), an intronic translocation of Cholinergic Receptor Nicotinic Alpha 3 Subunit (CHRNA3; P =.037), an intergenic translocation of Glutamate Ionotropic Receptor NMDA Type Subunit 2A (GRIN2A; P =.044), and an intronic insertion in Glutamate Metabotropic Receptor 5 (GRM5; P =.029) were found. Beyond these significant genes, an additional 6 genes in the same pathway had SVs which trended toward significance.

The investigators observed that the 686 and 439 ADHD-associated SV-genes among Black and White individuals, respectively, had little overlap, sharing only 34 genes between the 2 groups. Among all identified genes, only 4 had previously been associated with ADHD in previous studies.

In general, significant genes identified with a pooled analysis were only significant within either Black or White cohorts. For example, the intergenic variant identified in Myosin Binding Protein C1 (MYBPC1) reached a significance level of P =.017 among all individuals. However, within the ancestry analysis, the same variant had a significance level of P =.79 among Black and P =.0032 among White individuals, suggesting that genetic background is an important cofactor for ADHD SVs.

A limitation of this study was the imbalance of sample size between ethnic groups. However due to the high cost of whole genome sequencing, including more samples was not feasible.

These data indicated that non-coding variants may be important for the genetics of ADHD and that ethnicity was a significant underlying factor. Most interestingly was the identification of a single pathway in which Black and White individuals had differing structural variants in various genes, indicating the importance of this pathway for ADHD.

Reference

Liu Y, Chang X, Qu H, et al. Non‑coding structural variation differentially impacts attention‑deficit hyperactivity disorder (ADHD) gene networks in African American vs Caucasian children. Sci Rep. 2020;10(1):15252. doi: 10.1038/s41598-020-71307-0