Exploring the Genetic Variants Associated with Brain Growth in Children

Understanding the genetic factors that control brain growth during childhood and adolescence is a priority for neuroscience. Its importance lies partly in the finding that disturbances in the course of brain development characterizes many common childhood behavioral problems. Recent advances in neuroimaging such as the use of non-invasive magnetic resonance imaging have provided a chance to define these trajectories in the living child. The intramural programs of the NIMH and NHGRI have conducted repeated neuroanatomic imaging on children along with the banking of DNA, providing a cohort which is studied for defining developmental trajectories of the brain. A central goal of this cohort is to define the disturbances in brain development that are linked with common behavioral problems, such as excessive impulsivity, hyperactivity and inattention. Studies have demonstrated that problems in these domains are distributed across the entire population and that children with Attention Deficit Hyperactivity Disorder (ADHD) lie at the extreme end of these behavioral dimensions. We found a similar dimensionality in the development of brain regions that are associated with these behavioral problems. Specifically, we showed that the rate of change in both the lateral prefrontal cortex and interconnected striatum during childhood and adolescence was linked to the severity of symptoms of hyperactivity and impulsivity. As symptoms increased, the rate of growth of both structures decreased. The lateral prefrontal cortex and striatum are core components of richly interconnected 'loops' that support a host of cognitive processes, including attention, cognitive control and motor planning. Anomalies in these structures and their connections have been implicated in many childhood behavioral problems, including ADHD. In summary, we aim to identify the common and rare genetic variants that are associated with the developmental trajectories of the lateral-prefrontal cortex and striatum. Identifying genetic variants influencing the growth of these structures may reveal the biological mechanisms underlying dysregulated control of attention, impulse and activity level, which in the extreme constitute ADHD. The study thus could inform our understanding of neurobiology underpinning one of the most common neuropsychiatric disorders of childhood.]]>
The cohort comprises children recruited from the Maryland/Virgini/DC area by advertisements and community links. Study entry (age at first clinical assessment) had a lower age range of 4 years and an upper limit of 21years. There was no set upper limit to age at final assessment. All subjects had at least two neuroanatomic magnetic resonance images. All races and ethnicities were included. The cohort is enriched for those at the extreme end of behavioral problems. Thus 122 (26%) of the cohort had problems with hyperactivity, impulsivity and inattention so severe that they met DSM-IVR criteria for Attention Deficit Hyperactivity Disorder. This enriched representation of the extremes of the behavioral dimension increases the variance of the brain phenotype. As a result, the cohort includes more males than females, reflecting the increased prevalence of ADHD and related behavioral problems in boys. Exclusion criteria were (1) intelligence quotient below 70 (assessed using age appropriate versions of the Wechsler intelligence scales); (2) any major physical or neurological illnesses; (3) Psychiatric diagnoses (other than ADHD, oppositional defiant disorder or conduct disorder at study entry); (4) psychotropic medications other than psychostimulants at study entry. ]]>
As noted earlier, the study reflects work conducted within the intramural programs of the NHGRI and NIMH.]]>