Rare Recurrent Variants in Noncoding Regions Impact Attention-Deficit Hyperactivity Disorder (ADHD) Gene Networks in Children of both African American and European American Ancestry.

Yichuan Liu,Patrick Sleiman,Hui-Qi Qu,Dong Li,Haijun Qiu,Xiao Chang,Joseph Glessner,Hakon Hakonarson,Lifeng Tian,Jingchun Qu

doi:10.3390/genes12020310

Yichuan Liu, Patrick Sleiman + Show 8 more

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https://doi.org/10.3390/genes12020310

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Abstract

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with poorly understood molecular mechanisms that results in significant impairment in children. In this study, we sought to assess the role of rare recurrent variants in non-European populations and outside of coding regions. We generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The cases included 116 African Americans (AA) and 89 European Americans (EA), and the controls included 408 AA and 262 EA. Multiple novel rare recurrent variants were identified in exonic regions, functionally classified as stop-gains and frameshifts for known ADHD genes. Deletion in introns of the protocadherins families and the ncRNA HGB8P were identified in two independent EA ADHD patients. A meta-analysis of the two ethnicities for differential ADHD recurrent variants compared to controls shows a small number of overlaps. These results suggest that rare recurrent variants in noncoding regions may be involved in the pathogenesis of ADHD in children of both AA and EA ancestry; thus, WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD.

Highlights

Previous studies suggest that Attention-deficit hyperactivity disorder (ADHD) is more likely to be regulated and impacted at the level of biological pathways instead of an individual gene [2,39]
Our previous study in these subjects replicated multiple copy number variation (CNV) associated with ADHD from previous studies, and we identified clustering of noncoding structural variations (SVs) in neuroactive ligand–receptor interaction pathways [40]
Previous studies are highly focused on single-nucleotide variants (SNVs) in coding regions; on the other hand, noncoding genomic structural variations and noncoding genes have been shown to play important roles in many human diseases, including other neurodevelopmental diseases such as autism and intellectual disability [41]

Summary

Introduction

A meta-analysis of the two ethnicities for differential ADHD recurrent variants compared to controls shows a small number of overlaps These results suggest that rare recurrent variants in noncoding regions may be involved in the pathogenesis of ADHD in children of both AA and EA ancestry; WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD. Previous studies were highly focused on the coding regions of the genome, and no systematic genetic studies have been conducted in ADHD patients of ethnicities other than European Caucasian To address these limitations of previous studies, we performed deep whole genome sequencing (WGS) in 875 individuals, including 205 ADHD patients and 670 non-ADHD controls, in order to assess the impact of variants in noncoding regions on the molecular published maps and institutional affiliations.

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