Genetic, Brain Structure, and Environmental Effects on ADHD

OBJECTIVES:

This study aims to provide novel phenotypes for genomic studies into Attention- Deficit
Hyperactivity Disorder (ADHD), one of the most common and heritable of all neuropsychiatric
disorders. It proposes to split the disorder into neurobiologically more meaningful entities
by delineating subgroups based on neurobehavioral profiles. It will also explore factors that
impact clinical course, focusing on the neural effects of treatment and the role of the child
s social environment.

POPULATION AND DESIGN:

Using a prospective longitudinal design, a group of children and adolescents with ADHD will
be followed. Additionally, families that have several members affected by ADHD will be
recruited.

OUTCOMES:

The study will link the onset and clinical course of ADHD with genotype, brain structure and
function, behavior and the child s social environment.

- INCLUSION CRITERIA FOR ALL PARTICIPANTS:

Three or more years of age with no upper limit for age at time of enrollment. The lower
limit of 3 years of age is chosen as it is difficult to diagnose ADHD below this age, but
the diagnosis can be reliably made from age 3 onwards. As this study examines the
developmental trajectories of ADHD into adulthood, no upper age limit has been set.

INCLUSION CRITERIA FOR CLINICAL POPULATIONS:

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) defined
ADHD. The DSM-IV diagnosis of ADHD will be based on the Parent Diagnostic Interview for
Children and Adolescents in participants 18 years or age and younger and the Schedule for
the Diagnosis of DSM Disorders for participants above 18 years of age. For those of school
age, an additional inclusion criterion is the Conners' Teacher Hyperactivity rating greater
than 1.5 standard deviations above age- and sex-specific means. ADHD is rarely found in
isolation and comorbidity is common. Thus the protocol will include individuals with ADHD
and the

following disorders: oppositional defiant disorder, conduct disorder, anxiety disorders
(generalized anxiety, specific phobias), tic disorders, mood disorders (dysthymia,
depression); specific learning disabilities.

In studying the acute effects of treatment we will include all participants with ADHD who
are starting psychostimulant medications for the first time (all psychostimulant
preparations are included). We will also include participants with ADHD who are receiving
behavioral

management for ADHD for the first time.

INCLUSIONS CRITERIA FOR THE FAMILY STUDY:

We will also include families where there is a incidence of >30% of ADHD in first, second
and third degree relatives. This level is chosen as it is well above the incidence rate of
ADHD in the general population (~5-7%). Additional inclusion criteria are families where
the proband has at least one sibling and only one or neither parent is affected.

We have already identified families of our currently enrolled probands in which at least 4
other first, second or third degree relatives have a current diagnosis of ADHD or had this
diagnosis in childhood (and have a similar number of unaffected relatives). We will recruit
further families with a similar density of individual affected by ADHD.

EXCLUSION CRITERIA FOR ALL PARTICIPANTS:

Full scale IQ of less than 70. Below this level a child is considered to have global
intellectual disability (classified in DSM-IVR as mental retardation). By definition this
means the individual cannot be considered to be a healthy control . While many individual
with IQ below 70 have symptoms of ADHD, the diagnosis is complicated by problems in
assessing attentional abilities.

Finally, there are often issues around the ability to give informed consent in adults with
global intellectual disability.

Birth before 32 weeks of gestation. Premature birth can have a profound effect on brain
function and structure.

Presence or history of medical conditions that are known to cause alterations in cerebral
anatomy detectable by neuroimaging that is current accepted clinical use. Examples include
a history of stroke, arteriovenous malformations, agenesis of the corpus callosum, history
of neurosurgery, hydrocephalus. Genetic syndromes which are associated with well
established alterations of gross cerebral structure- such as NF1, tuberous sclerosis and
some forms of epilepsy. Children with known microdeletion syndromes will not be excluded
provided (1) the syndrome is not known to be associated with alteration of cerebral anatomy
(detectable on current clinical MRI sequences) and (2) other exclusionary criteria do not
apply such as global intellectual impairment (defined in this protocol as IQ above 70).
Data from these individuals with microdeletion syndromes will not however be included in
GWAS due to analytic complications.

Dental braces (as these distort the MRI image). Metal in the body or other
contraindications for MRI scanning.

Females who are pregnant will not participate in the MRI scanning only. They will be able
to participate in all other parts of the study and can complete the MRI scan post-partum.
For participants 60 years or older. Folstein mini mental state examination score of 26 or
greater. This is a widely accepted screening test for dementia.

ADDITIONAL EXCLUSION CRITERIA FOR HEALTHY VOLUNTEERS ONLY: Presence of any DSM-IV
psychiatric disorder in the subject or current use of psychiatric medication.

ADDITIONAL EXCLUSION CRITERIA FOR THE CLINICAL POPULATION ONLY:

Some neuropsychiatric disorders are either so rare or associated with such profound
alterations of brains structure and function that they will be excluded. This includes
psychotic disorders (including schizophrenia, psychosis NOS) bipolar affective disorder;
autism, substance dependence; dementia.