Genetic Overlap Between Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in SHANK2 Gene.

Suk-Ling Ma,Timothy S H Mak,Flora Mo,Pak-Chung Sham,Lu Hua Chen,Chi-Chiu Lee,Chun-Pan Tang,Kelly Y C Lai,Caroline Shea,Ting-Pong Ho,Se-Fong Hung,Patrick W L Leung

doi:10.3389/fnins.2021.649588

Abstract

Background: Recent findings indicated a high comorbidity between attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), as well as shared genetic influences on them. The latter might contribute at least partly to the former clinical scenario. This study aimed at investigating whether SHANK genes were potential pleiotropic genes to the two said disorders, underlying their genetic overlap.Methods: This study recruited 298 boys with ADHD (including 256 family trios of 1 ADHD boy and his 2 biological parents), 134 boys with ASD, 109 boys with both ADHD and ASD, and 232 typically developing boys as community controls. They were aged between 6 and 11 years old.Results: There was no significant difference in allele frequency of a number of single nucleotide polymorphisms (SNPs) in SHANK2/SHANK3 between the three clinical groups (ADHD, ASD, and ADHD + ASD) and between the two control groups (community controls and pseudo-controls), respectively. The three clinical groups and the two control groups were thus, respectively, combined. A comparison between the two aggregated samples identified significant evidence of disease association for three SHANK2 SNPs with both ADHD and ASD, even after multiple testing correction: rs11236616 (OR = 0.762, permuted p = 0.0376), rs7106631 (OR = 0.720, permuted p = 0.0034), and rs9888288 (OR = 0.770, permuted p = 0.0407). Comparisons among individual groups pointed to a similar trend of findings.Conclusion: SHANK2 could be considered a potential pleiotropic gene underlying the genetic overlap between ADHD and ASD. This might contribute partly to their high comorbidity in the afflicted children.

Highlights

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two separate common neurodevelopmental disorders in children. Their diagnoses were previously hierarchical such that a diagnosis of ASD precluded a diagnosis of ADHD
The two disorders were found conceptually distinctive and empirically separable by a two-factor common pathway model, while the elevated ASD traits in ADHD children could not be explained by ADHD or other associated behavioral symptoms (Grzadzinski et al, 2011; Ronald et al, 2014)
SHANK2−/− knock-out mice displayed both hyperactive and autistic-like behavior (Schmeisser et al, 2012). Based on these lines of existing evidence, the present study aims at testing SHANK2 and SHANK3 for pleiotropic effects by examining their common variants (SNPs) for association with both ASD and ADHD

Summary

Introduction

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two separate common neurodevelopmental disorders in children. Their diagnoses were previously hierarchical such that a diagnosis of ASD precluded a diagnosis of ADHD. 20–50% of ADHD children met diagnostic criteria for ASD, while 30–80% of ASD children met diagnostic criteria for ADHD (Simonoff et al, 2008; Sinzig et al, 2009) This high comorbidity cannot be explained by diagnostic or phenotypic overlap. Recent findings indicated a high comorbidity between attentiondeficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), as well as shared genetic influences on them. The latter might contribute at least partly to the former clinical scenario. This study aimed at investigating whether SHANK genes were potential pleiotropic genes to the two said disorders, underlying their genetic overlap

Objectives

Methods

Results