Advancing Understanding of Genomic Mechanisms for Primary ADHD in Families

ABSTRACT The genetic mechanisms contributing to neurodevelopmental disorders are highly variable across children and families. This is especially true for attention-deficit/hyperactivity disorder (ADHD), which affects approximately 7% of school aged children. In the last decade, databases containing genomic information about individuals and families with ADHD have been developed. However, the individuals within these databases are highly heterogeneous, due to varying recruitment methods, ADHD diagnosis, and variable inclusion/exclusion criteria. For example, some individuals with ADHD may have comorbid autism (ASD) or intellectual disability (ID), and many individuals self-report their ADHD status, without a standardized approach to confirming the diagnosis. As a result, much of the underlying genetic etiology of well-defined primary ADHD (i.e., ADHD without comorbid ID or ASD) remains unknown. Common variants account for a minority of variance in ADHD, and our pilot data suggests that up to 50% of individuals with primary ADHD have a rare pathogenic variant accounting for their diagnosis. We aim to improve the understanding of the genetic underpinning of primary ADHD through the following major goals: 1) Developing the largest family-based repository of children with primary ADHD and their family members using consistent, precise, and comprehensive diagnostic criteria, as well as standardized evaluations of parental and sibling ADHD status. 2) Identify novel candidate genes for ADHD and expand on previous studies that have focused on de novo (spontaneous) genetic mutations, by also examining co-segregation of ADHD and inherited genetic variants, thereby providing the most comprehensive analysis of the genomic architecture of ADHD to date. 3) Validate our gene discovery by assessing genome-wide significance in an existing sample of 5,595 cases and 62,739 healthy controls. 4) Develop a more robust clinical variant classification approach through integrated family histories and functional studies that will increase understanding of the impact of variants of unknown significance and will provide a valuable resource for future genomic and neurobiological functional studies. To do this, we will analyze genomic data from 1,400 children and their families who have been diagnosed with ADHD (without autism or intellectual disability) using comprehensive neuropsychological evaluation from two sources: 402 from our own Developmental Medicine Center (DMC) at Boston Children's Hospital, including 187 already recruited; and 998 from the IMAGE Study, for which data is available through the NIH RGR. We will validate our findings in a sample of 5,595 cases and 62,739 controls from the NIH All of Us Research Program. We will conduct whole exome sequencing (WES) on all participants, perform mRNA-sequencing from hiPSC- derived neural cells to clarify the impact of a subset of variants of unknown significance, and perform patient- and CRISPR-derived iPSC analyses on a subset of 5 damaging variants of interest.