The Section on Neurobehavioral Clinical Research was established in the Social and Behavioral Research Branch of the NHGRI in October 2011. We focus on one of the most common and heritable of all neuropsychiatric disorders of childhood, Attention Deficit Hyperactivity Disorder (ADHD). The overarching goal is to determine how the developmental course of ADHD is shaped by the interplay of genomic, neural and interpersonal processes. ADHD is a prevalent disorder that affects 7-10% of children and 3% of adults worldwide. ADHD entails substantial economic costs ( $140 billion/year in the US), causes great personal and familial distress, and impairs academic and occupational functioning into adulthood. The disorder is also a major risk factor for criminal behavior, substance misuse and mood disorders. The protocol supports an active clinical research unit which in the past year has assessed 225 new participants and a further 103 returned for reassessment. All participants- children with ADHD, their families and typically developing children - have clinical, behavioral, neuropsychological assessments along with brain imaging (using a magnetic resonance scanner). These assessments are repeated yearly as the child grows into adolescence and adulthood and we started to collect detailed behavioral and social data on all participants including details of friendships and the family environment. Research accomplishments. 1) The developing brain in ADHD. Our group has completed a series of studies defining brain development in ADHD. We have focused on the adult outcome of ADHD, demonstrating that the divergent clinical outcomes of ADHD in adolescence and adulthood are linked with divergent trajectories of cerebral cortical development. Secondly, we have used recent advances in neuroimaging to begin to define the connectome in ADHD. Finally, we have demonstrated that many of the neurodevelopmental trajectories that characterize the disorder of ADHD behave as quantitative traits and are found in an attenuated form in children who have some symptoms of ADHD not severe enough to warrant any diagnosis. In the past year we also focused on linking brain and behavior. For example, when children have problems with motor coordination, they often have problems with attention and impulse control. Thus, 50% of children with Attention Deficit Hyperactivity Disorder (ADHD) meet criteria for Developmental Coordination Disorder, and vice verse. This overlap has been viewed as delineating a subtype of ADHD with a distinct natural history and genetic basis. We thus mapped the neuroanatomic substrate of motor coordination in 220 children, asking whether this substrate differs in children with ADHD compared to those without. We found that the motor coordination skills were significantly associated with the dimensions of regions within both the cerebral cortex and the cerebellum. This effect was driven by the dimensions of the premotor/motor cortical regions and the superior cerebellar lobules, implicating these regions as pivotal in motor coordination. Importantly, these links were independent of the diagnosis of ADHD, demonstrating that the neuroanatomic substrate of motor coordination does not differ in the context of ADHD. 2) Problems with the regulation of emotions in ADHD. It has long been recognized that many individuals with ADHD also have difficulties with emotion regulation. We have worked with leading experts in this area at NIMH (Dr Leibenluft) and the Institute of Psychiatry, London (Dr Stringaris) to develop a conceptual framework for studying this clinically challenging domain. As an extension of this work, we are linking problems with emotion regulation with underlying brain systems. 3) Ongoing genomic projects. Monozygotic twins are largely identical in their genetic makeup, but can differ considerably in their epigenome (the modifications made in response to experience that alter gene expression). We screened over 300 pairs of MZ twins to identify 13 pairs in which one twin had ADHD and the other completely was unaffected. We are currently examining epigenetics modifications across the entire genome to determine if these contribute to the discordance for ADHD. In a second project, we are now looking for genetic variants that influence the growth of brain structures that appear to be critical for ADHD the prefrontal cortex and the interconnected striatum. We are thus mapping genetic variation throughout the entire genome and determining how this impacts on growth rates of the developing brain. This could throw light onto the biological mechanisms underlying dysregulated control of impulses and attention. 4) Ongoing social scientific projects. Peer relationships are important for childrens mental health, yet little is known of their etiological underpinnings. Thus we have explored the genetic influences on childhood peer network characteristics in three different networksdefined by rejection, acceptance, and prosocial behavior. We further defined the impact of early life mental health trajectories on these same peer network characteristics. Specifically, we ask if the developmental trajectories of preschool externalizing and internalizing behavior are uniquely linked to a childs later role within peer networks. Externalizing behaviors include the behavioral symptoms most characteristic of ADHD. To achieve this goal we worked collaboratively with colleagues in the Netherlands (the Generation R study). We mapped out the classroom peer networks of over 1,200 children, for peer rejection, acceptance, and prosocial behavior using mutual peer nominations. Genetic influences on childrens peer network characteristics were estimated from DNA using genome-wide complex trait analysis. Developmental trajectories of preschool externalizing and internalizing behavior were computed using parental ratings at ages 1.5, 3 and 5 years. We found that of the three network properties examined, closeness centrality emerged as significantly heritable across all networks. Preschool externalizing problems predicted unfavorable positions within peer rejection networks and having fewer mutual friendships. In contrast, children with preschool internalizing problems were not actively rejected by their peers but were less well connected within their social support network. This work joins recent methodological advances in genomics in orienting us to the role of genes in shaping a childs position within peer networks; while network perspectives offer rich insights into how early externalizing and internalizing problems impact a childs later functioning within peer networks.

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Park, Min Tae M; Raznahan, Armin; Shaw, Philip et al. (2018) Neuroanatomical phenotypes in mental illness: identifying convergent and divergent cortical phenotypes across autism, ADHD and schizophrenia. J Psychiatry Neurosci 43:170094
White, Tonya; Jansen, Philip R; Muetzel, Ryan L et al. (2018) Automated quality assessment of structural magnetic resonance images in children: Comparison with visual inspection and surface-based reconstruction. Hum Brain Mapp 39:1218-1231
Kong, Xiang-Zhen; Mathias, Samuel R; Guadalupe, Tulio et al. (2018) Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium. Proc Natl Acad Sci U S A 115:E5154-E5163
Chen, Y-C; Sudre, G; Sharp, W et al. (2018) Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder. Mol Psychiatry 23:683-690
Shaw, Philip; Ishii-Takahashi, Ayaka; Park, Min Tae et al. (2018) A multicohort, longitudinal study of cerebellar development in attention deficit hyperactivity disorder. J Child Psychol Psychiatry 59:1114-1123
Szekely, Eszter; Sudre, Gustavo P; Sharp, Wendy et al. (2017) Defining the Neural Substrate of the Adult Outcome of Childhood ADHD: A Multimodal Neuroimaging Study of Response Inhibition. Am J Psychiatry 174:867-876
Shaw, Philip; Ahn, Kwangmi; Rapoport, Judith L (2017) Good News for Screening for Adult Attention-Deficit/Hyperactivity Disorder. JAMA Psychiatry 74:527
Sudre, Gustavo; Choudhuri, Saadia; Szekely, Eszter et al. (2017) Estimating the Heritability of Structural and Functional Brain Connectivity in Families Affected by Attention-Deficit/Hyperactivity Disorder. JAMA Psychiatry 74:76-84
Hoogman, Martine; Bralten, Janita; Hibar, Derrek P et al. (2017) Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. Lancet Psychiatry 4:310-319
Shaw, Philip (2016) Quantifying the Benefits and Risks of Methylphenidate as Treatment for Childhood Attention-Deficit/Hyperactivity Disorder. JAMA 315:1953-5

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