Abstract
Previous studies of attention-deficit hyperactivity disorder (ADHD) have suggested that structural variants (SVs) play an important role but these were mainly studied in subjects of European ancestry and focused on coding regions. In this study, we sought to address the role of SVs in non-European populations and outside of coding regions. To that end, we generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The ADHD cases included 116 African Americans (AA) and 89 of European Ancestry (EA) with SVs in comparison with 408 AA and 262 controls, respectively. Multiple SVs and target genes that associated with ADHD from previous studies were identified or replicated, and novel recurrent ADHD-associated SV loci were discovered. We identified clustering of non-coding SVs around neuroactive ligand-receptor interaction pathways, which are involved in neuronal brain function, and highly relevant to ADHD pathogenesis and regulation of gene expression related to specific ADHD phenotypes. There was little overlap (around 6%) in the genes impacted by SVs between AA and EA. These results suggest that SVs within non-coding regions may play an important role in ADHD development and that WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD
Highlights
Previous studies of attention-deficit hyperactivity disorder (ADHD) have suggested that structural variants (SVs) play an important role but these were mainly studied in subjects of European ancestry and focused on coding regions
In addition to the 37 exonic/splicing structural variations (SVs) that associated with ADHD we identified 451 rare ADHD-associated SVs in AA (Supplementary Table 2a) and 382 in European Ancestry (EA) (Supplementary Table 2b), 41 SVs are only existed in ADHD cases and were absent from controls (Table 2)
We identified 37 exonic/splicing SVs, several involving genes that have been previously reported in neurological and mental diseases, such as VPS53, which has been previously associated with a neurological conditions and Parkinson disease[18]
Summary
Previous studies of attention-deficit hyperactivity disorder (ADHD) have suggested that structural variants (SVs) play an important role but these were mainly studied in subjects of European ancestry and focused on coding regions. There was little overlap (around 6%) in the genes impacted by SVs between AA and EA These results suggest that SVs within non-coding regions may play an important role in ADHD development and that WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD. Genomic structural variations and non-coding DNA sequences have been shown to play important roles in many human diseases, including neurodevelopmental diseases such as autism and intellectual d isability[11,12] In this regard, the most recent large GWAS studies on 55,374 individuals, including 20,183 ADHD patients, highlighted that variants in non-coding regions, such as non-coding RNA and intergenic region were significantly associated with ADHD s usceptibility[13]. This information would be useful for future studies of ADHD genetic network regulation and drug development
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
