Genetic Analysis of Attention Deficit Hyperactivity Disorder (ADHD)

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood

disorders and the most common childhood neurodevelopmental behavioral disorder. Symptoms
include difficulty staying focused (inattention), difficulty controlling behavior
(impulsivity), and hyperactivity. Symptoms typically develop between six and 12 years of age,
and frequently persist into adulthood, with serious life-long health and social consequences.
Affected children are at increased risk for poor educational achievement, low income,
underemployment, legal difficulties, and impaired social relationships. The general belief is
that ADHD is caused by a combination of genetic and environmental factors.

The main objective of the study is to conduct genetic and behavioral studies that will
closely

characterize the genetic influences in diagnosis, prognosis, severity, and pharmacological

response in ADHD patients. Since the start of the study in 2000, research has contributed to
the understanding of the innate susceptibility of ADHD and associated comorbidities; the
interaction of genetic, demographic, and environmental factors underpinning the risk of
developing ADHD; the extent to which these factors shape the response of ADHD patients to
pharmacological interventions (pharmacogenetics); the over-representation of functional and
ontological genebased networks implicated in determining synapse structure; and the use of
advanced geneticepidemiological models with potential for use in clinical practice
(translational genomics). The most significant research finding occurred in 2010, when the
study team identified LPHN3, a key gene involved in the etiology of ADHD and comorbid
conditions in one of the previously identified regions of strong genetic signal in chromosome
4q13.2.

In order to provide power for the study s statistical analyses, the upper enrollment goal is
4,000 participants. Although the study has several small and genetically distinct cohorts,
the majority of subjects come from the United States of America population through outreach
recruitment efforts. Recruitment has been very successful and the large cohort numbers
provide support for identification of genetic components related to the diagnosis of ADHD.
Recent efforts have focused on identifying new areas of the genome associated with ADHD, and
identifying genetic (coding and non-coding) variations implicated in the etiology and
clinical manifestations of ADHD. A primary aim of the study is to correlate genetic and
biological markers for diagnosis and prognosis of ADHD identified through the use of state of
the art genomics, which includes enome-wide association studies, linkage analysis, whole
genome and exome sequencing, and targeted gene capture in cosmopolitan and isolated
populations. As the current diagnosis of ADHD is based on subjective observations, one of the
main goals of the study is to develop a more definitive system to diagnose ADHD and to assess
and predict prognosis.

- INCLUSION CRITERIA:

This study will enroll families with the following characteristics:

1. Families with children, seven through 17 years of age, diagnosed with ADHD (defined as
the proband for the study).

2. The probands siblings, either affected with ADHD (concordant) or unaffected
(discordant), seven years of age and above, including adult siblings.

3. The parents, both mothers and fathers, of enrolled probands.

4. The study will enroll both male and female probands of any ethnic background and race.
The prevalence of ADHD is higher in males than in females, so we would expect to have
a higher number of male probands than female probands. Both male and female siblings
and male and female parents of probands will be enrolled.

5. Adults who are or may be unable to provide informed consent will be excluded.

6. Probands with one parent affected with ADHD or with neither parent affected with ADHD
are eligible. Probands from bilineal families, families with both parents affected
with ADHD, will be excluded for statistical reasons.

Additional inclusion criteria for the study include:

1. Ability to read and understand spoken English, since the questionnaires, scales, and
interviews that we have license to use in this study are in English.

EXCLUSION CRITERIA:

Some conditions can confound the diagnosis of ADHD. Probands with the following conditions
will be excluded from enrollment or will be withdrawn from the study if the condition is
discovered subsequent to enrollment:

- Prematurity

- Neurological conditions

- Cardiac surgery

- Prenatal drug exposure

- Hydrocephaly

- Mental Retardation (IQ<80)

- Known genetic syndromes

- Known CNS disorders

- Known lead toxicity

- Tourette Disorder

- Obsessive-Compulsive Disorder

- Major Depression on both proband and affected sibling

- Pervasive Developmental Disorder

- Age under 7 years old

- Autism

- Other Psychoses

- Post Traumatic Stress Disorder

- Language Disorder (if known)

- Severe Sensory Impairment (visual and hearing)

Probands with the following conditions may be included, but the conditions will be noted
during statistical analysis:

- Oppositional Defiant Disorder

- Conduct Disorder

- Tic Disorder

- Obsessive/Compulsive Symptoms

- Anxiety/Phobias

- Learning Disabilities