rare misspellings of the genome, dopamine mishandling, and adhd

45 Pages·2017·6.31 MB·English

RARE MISSPELLINGS OF THE GENOME, DOPAMINE
MISHANDLING, AND ADHD
RANDY D. BLAKELY, PH.D.
FLORIDA ATLANTIC UNIVERSITY BRAIN INSTITUTE
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Dr. Blakely declares no conflicts of interest derived
from financial support of the research to be
discussed
Dr. Blakely has consulted on research projects in the
past for Amgen, Forest Research Institute,
Lundbeck, Jubilant Innovation, Pfizer, Prexa, and
Wyeth
CONFLICTS OF INTEREST
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ACKNOWLEDGEMENTS
Blakely Lab Collaborators
Lorena Areal Marc Mergy Erica Bowton Doug McMahon
Gwynne Davis Rodenia Pert Steve Couch Richard Shelton
Raaj Gowrishankar Max Rabil Heng Dai Harald Sitte
Paul Gresch Nathan Richtand Cristina Fenollar -Ferrer Gregg Stanwood
Maureen Hahn Justin Riele Michael Freissmuth Mark Stein
Rania Katamish DJ Sakrikar Aurelio Galli Roxanne Vaughan
Michelle Mazei-Robison Keeley Spiess Stephanie Gantz John Williams
Felix Mayer Adele Stewart Jonathan Javitch
Michael Gill Jeremy Veenstra-VanderWeele
Peter Hamilton Austin Wheeler
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ACKNOWLEDGEMENTS
Blakely Lab Collaborators
Lorena Areal Marc Mergy Erica Bowton Doug McMahon
Gwynne Davis Rodenia Pert Steve Couch Richard Shelton
Raaj Gowrishankar Max Rabil Heng Dai Harald Sitte
Paul Gresch Nathan Richtand Cristina Fenollar -Ferrer Gregg Stanwood
Maureen Hahn Justin Riele Michael Freissmuth Mark Stein
Rania Katamish DJ Sakrikar Aurelio Galli Roxanne Vaughan
Michelle Mazei-Robison Keeley Spiess Stephanie Gantz John Williams
Felix Mayer Adele Stewart Jonathan Javitch
Michael Gill Jeremy Veenstra-VanderWeele
Peter Hamilton Austin Wheeler
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OUTLINE
ADHD: Diagnosis, Genetics and Dopamine
Involvement
Identification of Mutations in the Human
Dopamine Transporter (DAT) in Subjects
with ADHD
The In Vivo Consequences of DAT Val559:
From Biochemistry to Behavior and Novel
Biomarkers
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ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
The most commonly diagnosed neurobehavioral disorder in
children (8.4% ages 2-17, 5.4 million) in the U.S. have a formal
ADHD diagnosis (National Survey of Children’s Health 2016)
Diagnosed solely through behavioral observation, with
presentation of symptoms of inattention, impulsivity and
hyperactivity (by age 12, DSM-5). Male bias in diagnosis (~4:1)
Approximately 60% are treated by medication, 25% receive no
treatment of any form
Higher incidence of substance abuse, conduct disorders,
unemployment, incarceration if left untreated
BASIC FACTS AND STATISTICS
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ADHD: DSM-5 Diagnostic Criteria
Inattentive Hyperactive/Impulsive
Symptoms Symptoms
•Careless Mistakes
•Fidgeting
•Difficulty Sustaining Attention
•Inability To Stay Seated
•Not Seeming To Listen
•Moving Excessively
•Failing To Finish Tasks
•Difficulty Playing Quietly
•Difficulty Organizing
• On the Go
•Avoiding Tasks That Require
•Talks Excessively
Sustained Attention
•Blurting Out Answers
•Losing Things
•Difficulty Waiting Turns
•Easily Distracted
•Interrupting
•Forgetful
•
6 or more symptons per category
for 6 months or more
•
symptoms present in two or more
settings and prior to age 12
I C H
•
Symptoms disrupt normal
function/quality of life
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ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
Heritability estimated at 60-90%, common and rare gene
variation linked to neuronal development and synaptic function
Co-morbidity and co-occurrence: Bipolar Disorder and Autism
Shared genetic heritability with Bipolar Disorder, Major
Depression, and Schizophrenia (Brainstorm Consortium, 2018)
GENETIC ARCHITECTURE
Common genetic variation of small effect (GWAS)
Rare genetic variation of large effect (e.g. Fragile X mutation)
Rare genetic variation of small to moderate effect (risk factor)
ADHD GENETICS
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HUMAN BRAIN
100 BILLION NEURONS
DOPAMINE
DOPAMINE: KEY BRAIN NEUROTRANSMITTER
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Cue Saliency
DOPAMINE
Attention
Executive Function
Learning
Reward and
Motivation
Locomotor Activity
DA CORE FUNCTIONS PERTURBED IN ADHD
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