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Genetic Variations Influence Brain Changes in Patients with Attention Yadav et al. Translational Psychiatry (2021) 11:349 https://doi.org/10.1038/s41398-021-01473-w Translational Psychiatry REVIEW ARTICLE Open Access Genetic variations influence brain changes in patients with attention-deficit hyperactivity disorder Santosh K. Yadav1,AjazA.Bhat 1, Sheema Hashem1,SabahNisar1, Madeeha Kamal2,NajeebSyed3, Mohamed-Ramzi Temanni3, Rakesh K. Gupta4, Saddat Kamran 5, Muhammad Waqar Azeem6, Amit K. Srivastava7, Puneet Bagga8, Sanjeev Chawla9, Ravinder Reddy10, Michael P. Frenneaux11, Khalid Fakhro 12,13 and Mohammad Haris 1,14 Abstract Attention-deficit hyperactivity disorder (ADHD) is a neurological and neurodevelopmental childhood-onset disorder characterized by a persistent pattern of inattentiveness, impulsiveness, restlessness, and hyperactivity. These symptoms may continue in 55–66% of cases from childhood into adulthood. Even though the precise etiology of ADHD is not fully understood, it is considered as a multifactorial and heterogeneous disorder with several contributing factors such as heritability, auxiliary to neurodevelopmental issues, severe brain injuries, neuroinflammation, consanguineous marriages, premature birth, and exposure to environmental toxins. Neuroimaging and neurodevelopmental assessments may help to explore the possible role of genetic variations on ADHD neuropsychobiology. Multiple genetic studies have observed a strong genetic association with various aspects of neuropsychobiological functions, including neural abnormalities and delayed neurodevelopment in ADHD. The advancement in neuroimaging and 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; molecular genomics offers the opportunity to analyze the impact of genetic variations alongside its dysregulated pathways on structural and functional derived brain imaging phenotypes in various neurological and psychiatric disorders, including ADHD. Recently, neuroimaging genomic studies observed a significant association of brain imaging phenotypes with genetic susceptibility in ADHD. Integrating the neuroimaging-derived phenotypes with genomics deciphers various neurobiological pathways that can be leveraged for the development of novel clinical biomarkers, new treatment modalities as well as therapeutic interventions for ADHD patients. In this review, we discuss the neurobiology of ADHD with particular emphasis on structural and functional changes in the ADHD brain and their interactions with complex genomic variations utilizing imaging genetics methodologies. We also highlight the genetic variants supposedly allied with the development of ADHD and how these, in turn, may affect the brain circuit function and related behaviors. In addition to reviewing imaging genetic studies, we also examine the need for complementary approaches at various levels of biological complexity and emphasize the importance of combining and integrating results to explore biological pathways involved in ADHD disorder. These approaches include animal models, computational biology, bioinformatics analyses, and multimodal imaging genetics studies. Background Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous neurobiological disorder of inat- tention, impulsivity, and hyperactivity, affecting 5–7% of – Correspondence: Mohammad Haris ([email protected]) children worldwide1 4. Severity status and symptoms of 1Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar 2Department of Pediatrics, Sidra Medicine, Doha, Qatar ADHD vary throughout a person’s lifespan; however, Full list of author information is available at the end of the article © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Yadav et al. Translational Psychiatry (2021) 11:349 Page 2 of 24 adult individuals with ADHD show less noticeable signs of According to the American Psychiatric Association Diag- hyperactivity and impulsivity than pediatric patients with nostic and Statistical Manual, Fifth Revision (DSM-V), the ADHD5,6. ADHD may occur either as an isolated condi- current diagnostic criteria for ADHD include subjective tion or as comorbidity with other neurological, psychia- measurements of inattentiveness (six or more symptoms tric, and neurodevelopmental disorders7,8. The adverse of inattention) and hyperactivity and impulsivity (six or impact of ADHD on society is profound and multifaceted more symptoms of hyperactivity–impulsivity)4.Thissub- as it affects not only all aspects of a child’s life but also jective assessment in the decision-making process may those of siblings and parents, causing significant dis- promptly overestimate or underestimate the symptoms of turbances to routine family functioning9,10. Furthermore, ADHD, especially in the pediatric population resulting in there are financial burdens related to treatment costs and both overdiagnosis and misdiagnosis. reduced employment prospects11. Based on the severity of Clinical symptoms of ADHD are associated with aber- the ADHD disorder, it may affect the child’s performance rant structural and functional changes in the brain13. at school, and if not treated or left undiagnosed, it may Several neuroimaging studies have been performed to persist into adulthood, affecting both personal and pro- evaluate the anatomical, microstructural, functional, bio- fessional life11. chemical, and molecular changes in the brains of – Multiple factors contribute to ADHD symptoms, ADHD14 16. Numerous neural networks implicating including genetic predisposition, neurodevelopmental attention, executive and reward functions, and molecular issues, abnormal neuronal maturation, brain injury, pathways such as dopaminergic, adrenergic, serotonergic, environmental exposures, and consanguineous marriages. and cholinergic have been identified that play a critical A recent study by Posner et al. reported that environ- role in the pathophysiology of ADHD, and these pathways mental risk factors during prenatal, perinatal, and post- can be studied in great details because of the advances in natal stages contribute to the symptom of ADHD. The the field of neuroimaging17,18. Molecular genomic studies, prenatal and perinatal risk factors, including premature on the other hand, have observed a strong genetic influ- birth, low birth weight, history of maternal exposure to ence on ADHD with a heritability estimate rate between – tobacco, stress, trauma, and obesity, are substantially 70 and 90%19 21. Several candidate genes, variants, and associated with ADHD. Postnatal risk factors such as chromosomes associated with ADHD symptoms have trauma, parenting style, artificial coloring, and flavoring been found in multiple studies focussing on correlation, food agents, exposure to pollutants and pesticides can linkage, and meta-analysis investigating the genetic sus- exacerbate the symptoms of ADHD12 (Fig. 1). ceptibility of ADHD. Genome-wide association studies Despite advancements in the diagnosis of various neu- (GWAS) have found genomic DNA copy number variants rological and psychiatric disorders, the accurate and early and rare or large deletion/duplications in ADHD22,23. diagnosis of ADHD still poses a considerable challenge. Studies using fine-mapping linkage analysis found Fig. 1 Factors affecting ADHD pathophysiology. Different factors such as genetic, in particular, gene polymorphisms, environmental factors, psychological factors, individual factors such as age, abnormality in various neurological pathways such as dopaminergic and serotonergic, and comorbidity with multiple disorders are associated with symptoms of attention-deficit hyperactivity disorder. Yadav et al. Translational Psychiatry (2021) 11:349 Page 3 of 24 variation in the gene encoding for neuronal signaling as a gray matter and subcortical regions in different neurolo- – potential risk factor for ADHD24 26. Multiple gene poly- gical disorders, including ADHD. MRI studies in patients morphisms showed an association with changes in the with ADHD have shown lower overall brain gray matter – neuropsychobiological functions in ADHD27,28. Most of volume (3–5%) than controls31,38 40. Several meta- the individual candidate gene association studies in analyses studies using automated voxel-based morpho- ADHD have been conducted on a small sample size and metric analysis have been performed to explore the global – the reported variants were not strongly associated with and regional gray matter volume changes in ADHD41 44. the ADHD pathology. Also, a recent genome-wide asso- A meta-analysis, based on 14 studies, observed that ciation (GWAS) based meta-analysis study, performed in patients with ADHD demonstrated a reduced overall a significantly large sample size, did not observe any volume of gray matter, particularly in the right caudate association
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