Fact or Fiction:Biological/Genetic Basis of ADHD

James M. SwansonUniversity of California, Irvine

Professor of PediatricsDirector of UCI Child Development Center

UCI-CDC Studies of DRD4 & Molecular Genetics of ADHD

• LaHoste, Swanson, Wigal et al, 1996• Swanson, Sunohara, Kennedy et al, 1998• Swanson, Castellanos, Murias, Kennedy, 1998• Swanson, Sergeant, Taylor et al, 1998• Swanson, Flodman, Kennedy et al, 2000• Swanson, Oosterlaan, Murias et al, 2000• Sunohara, Roberts, Malone et al, 2000 • Swanson, Posner, Fusella at al, 2001• Swanson, Deutsch, Cantwell et al, 2001• Barr, Swanson, Kennedy, 2001• Ding, Chi, Grady et al, 2002• Swanson, Moyzis et al, 2002

UCI-CDC Studies of DRD4 & Molecular Genetics of ADHD

• Fosella, Sommer, Fan et al, 2002• Goldsmith, Crabbe, Dawson et al, 2003• Grady, Chi, Ding et al, 2003• Wang, Ding et al, 2004• Cornish, Manly, Savage et al, 2005• Leung, Lee et al, 2005• Stevenson, Asherson et al, 2005• Feng, Crosbie et al, 2005• Grady, Hakxhi et al, 2005• Grady, Moyzis, Swanson, 2005 • Preston, Kollins, Swanson et al, 2005• Hay, Bennett, Levy, Sergeant, Swanson, 2006

Neuropsychology and Brain Imaging of ADHD• Swanson, Posner et al, 1991• Craft et al, 1992• Nigg, Swanson, Hinshaw, 1997 • Swanson, Castellanos, Murias, Kennedy, 1998• Swanson, Sergeant, Taylor et al, 1998• Kupfer et al, 2000• Swanson, 2000• Swanson, Oosterlann, Murias et al, 2000• Volkow, Gatley, Fowler et al, 2000• Levy and Swanson, 2001• Volkow, Wang, Fowler et al, 2002

Neuropsychology and Brain Imaging of ADHD

• Volkow, Wang, Fowler et al, 2003• Volkow and Swanson, 2003• Swanson and Volkow, 2003• Swanson, 2003• Volkow, Wang, Ma et al, 2003• Volkow, Wang, Fowler, Swanson, 2004• Volkow, Wang, Fowler, Telang et al, 2004• Volkow, Wang, Ma et al, 2004• Volkow, Wang, Ma et al, 2005• Murias, Swanson, Srinivasan, 2006• Volkow, Wang, Newcorn, et al, 2007

RUTTER’S CHILD AND ADOLESCENT PSYCHIATRY, 5TH EDITION

Neurochemistry and Basic Psychopharmacology Volkow and Swanson, 2007 (in press)

Neuropsychology Review, 2007

Summary of A Decade of Research

ADHD

Historical Timeline

19601960 19801980

Minimal Brain Dysfunction

19681968

Hyperkinetic Reaction of Childhood (DSM-II)

Minimal Brain Damage

19871987 19941994

Attention Deficit Hyperactivity Disorder (DSM-III-R)

Attention Deficit Disorder + or - Hyperactivity (DSM-III)

Attention Deficit/Hyperactivity Disorder (DSM-IV)Attention Deficit/Hyperactivity Disorder (DSM-IV)

1930193019301930

ADHD: DSM-IV Criteria for Predominantly Inattentive Type

• Inattention to details/ makes careless mistakes

• Difficulty sustaining attention

• Seems not to listen

• Fails to finish tasks

• Difficulty organizing

• Avoids tasks requiring sustained attention

• Loses things

• Easily distracted

• Forgetful

Six or more of the following Six or more of the following manifested manifested oftenoften::

Inattention

American Psychiatric Association. DSM-IV, 1994.

ADHD: DSM-IV Criteria for Hyperactive-Impulsive Type

Six or more of the following Six or more of the following manifested manifested oftenoften::

Impulsivity/HyperactivityImpulsivity/Hyperactivity

ImpulsivityImpulsivity• Blurts out answer before

question is finished

• Difficulty awaiting turn

• Interrupts or intrudes on others

Hyperactivity• Fidgets• Unable to stay seated• Inappropriate running,

climbing (restlessness)• Difficulty in engaging in

leisure activities quietly• “On the go”• Talks excessively

American Psychiatric Association. DSM-IV, 1994.

Why do children manifest these symptoms of ADHD?Dopamine Theory of ADHD

(Wender, 1971; Levy, 1991; Swanson et a, 1998)

Site of Action Theory of Stimulant Medications(Posner and Raichle, 1994; Volkow et al, 1995; Volkow and Swanson, 2007)

SNVTA SNVTA

Posner and Raichle, Images of Mind, 1994 (Neuroanatomical Network Theory of Attention)

Alerting(ready for anything)

Right frontal

Orienting(prepared for

specific)Bilateral parietal

Executive Control

(control of conflict)Anterior cingulate

Swanson JM, et al. Attention deficit hyperactivity disorder. In: Wilson RA, Keil FC, eds. The MIT Encyclopedia of the Cognitive Sciences. Cambridge, MA: MIT Press; 2001:226.

SUMMARY OF MRI STUDIES: Smaller Brain Structures in Areas Related to

Movement and Attention

Hynd, 1993 19.0% SMALLER

Castellanos, 1996 5.4% SMALLER

Filipek, 1996 12.7% SMALLER

Aylward, 1996 11.8% SMALLER

Caudate Nucleus Anterior Prefrontal

Globus Pallidus Cerebellar Vermis VIII-X

Anatomical Sizes (Effect Size: Control–ADHD) Anatomical Sizes (Effect Size: Control–ADHD) Larger Posterior and Smaller Anterior RegionsLarger Posterior and Smaller Anterior Regions

1.25

1.00

.75

.50

.25

0

-.25

Effect Size

R L R L

Occipital

Rostral Corpus Callosum

Larger Than normal

SmallerThan Normal

Swanson JM, Casey BJ, Nigg J, Castellanos FX, Volkow ND, Taylor E. (2004).

The Dopamine Hypothesis:The Cellular Basis of the DA Deficit

RECEPTOR

TRANSPORTER

Positron Emission TomographyPositron Emission Tomography

(PET)(PET)

DA

signal

DA

DA

DA DA

MAO A

DA transporters [11C] MPH

DA D2 receptors[11C]raclopride

PET Measures1. DA Transporters2. DA D2 Receptors

DRD2DAT

Dopamine- Deficit Hypothesis of ADHD/HKD(based on stimulant drug site-of- action hypothesis)

Dopamine Transporter Density in Patients with ADHD (Dougherty et al, 1999)

“We have shown a 70% increase in age-corrected dopamine transporter density in patients with ADHD compared to healthy

controls”.

Volkow et al, 2007, NeuroImage 34: 1182-1190Brain DAT levels in treatment naïve adults with ADHD

Dopamine Transporter Levels Are Lower in Treatment Naïve Adults with ADHD

Positron Emission Tomography (PET) studies show that methylphenidate acts predominantly in the striatum of

the human brain where it binds to DA transporters

[11C]methylphenidate

methylphenidate

Extensive PET studies of Methylphenidate in the Human Brain

11C

Pharmacological Treatments of ADHD and Neuroanatomical Targets

• Multiple reviews of literature by early 1990s– Wilens and Biederman (1992)

• Psychiatric Clinics North America, “The Stimulants”

– Swanson et al (1993)• Exceptional Children, “Review of Reviews”

• Major change in early 2000 to controlled delivery– Swanson, Gupta et al (1999)

• Clin Pharm Ther, “Acute tolerance to MPH”

– Greenhill et al (2003)• JAACAP, “PK/PD of Adderall”

• Recent increase in non-stimulant medications

1. Threshold Dose

2. Brain Pharmacokinetics

3. Individual Differences

4. Context of Administration

Absorption (ka)

Distribution (ke)Elimination (keo)

Ce(t)

TransportersEnzymes

Receptors

Ee(t)

Emotion

Cognition

Side Effects

Synapse CircuitBlood Brain

C(t) E(t)

Pharmacokinetic Pharmacodynamic

Volkow and Swanson, 2007 (in press)RUTTER’S CHILD AND ADOLESCENT PSYCHIATRY,

5TH EDITION

Neurochemistry and Basic Psychopharmacology

Time (min)0 10 20 30 40 50 60 70 80

[11C]MP

0

20

40

60

80

100

"High"

PK half-life = 1.5 hr

Behavioral half-life ~ .3 hr

PET Imaging and Brain Pharmacokinetics of Methylphenidate (Volkow et al, 1995)

[11C]Methylphenidate

PET Studies of Mechanism of Action:

DAT Blockade by Oral MPH

Placebo

20 mg

40 mg

Volkow ND, et al. Synapse. 1999;31:59.Volkow ND, et al. Synapse. 2002;43:181.

0

20

40

60

80

100

0.0 0.2 0.4 0.6 0.8 1.0

DA

T O

cc

up

an

cy

(%)

Dose (mg/kg)

Typical dose(.3–.5 mg/kg)

DA

DA

DADA DADA

DA

DA

DA

DA

DA

DADADA

DADA

DADA MPDA

DADA DA

DA

Effects of Oral MP on Extracellular DAEffects of Oral MP on Extracellular DA

Placebo

Oral MP

2.5

3.0

3.5

4.0

Placebo MP

Bm

ax/k

d

p < 0.0005

Therapeutic doses of oral MP significantly increase extracellular DA in the human brain

Volkow et al. (2001) J Neuroscience, 21:1-5.

Methylphenidate (MPH) Blocks the Dopamine Methylphenidate (MPH) Blocks the Dopamine Transporter (DAT) and Increases SignalTransporter (DAT) and Increases Signal

DA

DA

DA

DA DA

MAO A

DA

DA

signal

DA

DA

DA

DA DA

MAO A

DA

DA

signal

DA

DA

DA

DADADA DA

DA

DA DA

DA

DA

DA

UNLABELED MPH

Brain areas with significantly changed cerebral blood flow (CBF) after methylphenidate treatment (assessed by paired t-test between baseline and posttreatment conditions) in ADHD patients. Red-yellow, increased CBF after treatment; blue-cyan, decreased CBF after treatment.Lee JS et al. Hum Brain Mapp. 2005;24:157-164.

P<.01

P<.05

+ 64 mm+ 42 mm - 8 mm - 18 mm - 40 mm

DA Deficit Hypothesis of ADHDDA Deficit Hypothesis of ADHD

SNVTA

DRD2DAT

Dopamine Receptor D4 (DRD4)

Dopamine Receptor D2 (DRD2)

Wender, (1971); Levy (1990)

Biological Bases of ADHD:The Dopamine Hypothesis

RECEPTOR

TRANSPORTER

D4 RECEPTORand the 48 bp Variable Number of Tandem Repeats (VNTR)

CCC-GCG-CCC-CGC-CTC-CCC-CAG-GAC-CCC-TGC-GGC-CCC-GAC-TGT-GCG-CCC

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

4 Repeat

7 Repeat

2 Repeat

DRD411p

Alleles of the DRD4 Gene for Possible Offspring

FatherAllele 1

FatherAllele 2

4-repeatallele

7-repeatallele

MotherAllele 1

4-repeatallele

4-repeat4-repeat

4-repeat7-repeat

MotherAllele 2

2-repeatallele

2-repeat4-repeat

2-repeat7-repeat

Molecular Genetic Approaches

.

Human DHuman D44 Gene PCRGene PCR

ADHD FamiliesADHD Families

PrimerSet.4: HDPrimerSet.4: HD44--2926 / HD2926 / HD44--3610R3610R

DRDDRD44--ExonIIIExonIII

bpbp 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414

G00010G00010 G00029G00029 G00048G00048

10

010

0 -- bp

DN

A l

ad

der

bp

DN

A l

ad

der

900900800800700700

600600

500500

1,0001,000

1,2001,200

400400

UCI-CDC Studies of DRD4 & Molecular Genetics of ADHD

• LaHoste, Swanson, Wigal et al, 1996• Swanson, Sunohara, Kennedy et al, 1998• Swanson, Castellanos, Murias, Kennedy, 1998• Swanson, Sergeant, Taylor et al, 1998• Swanson, Flodman, Kennedy et al, 2000• Swanson, Oosterlaan, Murias et al, 2000• Sunohara, Roberts, Malone et al, 2000 • Swanson, Posner, Fusella at al, 2001• Swanson, Deutsch, Cantwell et al, 2001• Barr, Swanson, Kennedy, 2001

GENOTYPE: 7-absent 7-present

ADHD

Control

51% 49%

79% 21%

Allele (number of repeats)

0

10

20

30

40

50

60

ADHDControl

2 4 7

Fre

quen

cy

LaHoste, Swanson…Kennedy, 1996, Molecular Psychiatry, 1:121-124 Swanson, Sunohara, Kennedy…, 1998, Molecular Psychiatry, 3: 38-41

DAT DRD4

> 1.0 = Risk

Genome Scans Followed the Candidate Gene Studies of ADHDRecent study identified 18 “risk” genes for ADHD

DRD4 and DAT genes confirmed and 16 other risk genes suggested

UCI-CDC Studies of DRD4 & Molecular Genetics of ADHD

• LaHoste, Swanson, Wigal et al, 1996• Swanson, Sunohara, Kennedy et al, 1998• Swanson, Castellanos, Murias, Kennedy, 1998• Swanson, Sergeant, Taylor et al, 1998• Swanson, Flodman, Kennedy et al, 2000

• Swanson, Oosterlaan, Murias et al, 2000• Sunohara, Roberts, Malone et al, 2000 • Swanson, Posner, Fusella at al, 2001• Swanson, Deutsch, Cantwell et al, 2001• Barr, Swanson, Kennedy, 2001

Components of Tasks Designed to Measure Executive Control

• Executive control deficits would produce:– In the Stroop Color-Conflict Task, an increased

cost of ‘incongruent’ and reduced benefits of ‘congruent’

– In the Posner Cued-Detection Task, increased costs of ‘Invalid’ or ‘No’ cues

– In Logan Go-Change Task, slow responding in the ‘change’ condition

Swanson et al. (2000) PNAS, 97:4754-4759ADHD children with a 7-repeat allele of the dopamine receptor D4 gene

have extreme behavior but normal performance on critical tests

Normal performance on critical neuropsychological tests

0

200

400

600

800

1000

1200

Stroop

Str

oo

p T

ask

RT

(m

s)

Posner200

250

300

350

400

450

500

550

600

Logan

Po

sner &

Lo

gan

Task

s RT

(ms)

7-

7+

Control

Average RT

Langley et al, American Journal Psychiatry, 2003 ADHD children with and without the dopamine D4 receptor 7-

repeat allele: Performance on neuropsychological tests 

TASK: Stop-RT (p<.029)

MFF-I (p<.001)

MFF-C (p<0.09)

7-present genotype

(n = 25)496 msec 846 msec 947 msec

7-absent genotype

(n = 50)572 msec 1103 msec 1155 msec

Next Questions

• Why does one allele (7R) of the DRD4 gene protect children with ADHD from cognitive deficits?

• Does the 7+ genotype confer some unusual advantage?

• Does the 7- genotype confer some disadvantage?

UCI-CDC Studies of DRD4 & Molecular Genetics of ADHD

• Ding, Chi, Grady et al, 2002• Swanson, Moyzis et al, 2002• Fosella, Sommer, Fan et al, 2002• Goldsmith, Crabbe, Dawson et al, 2003• Grady, Chi, Ding et al, 2003• Wang, Ding et al, 2004• Cornish, Manly, Savage et al, 2005• Leung, Lee et al, 2005• Stevenson, Asherson et al, 2005• Feng, Crosbie et al, 2005• Grady, Hakxhi et al, 2005 • Preston, Kollins, Swanson et al, 2005

D4 RECEPTORand the 48 bp Variable Number of Tandem Repeats (VNTR)

CCC-GCG-CCC-CGC-CTC-CCC-CAG-GAC-CCC-TGC-GGC-CCC-GAC-TGT-GCG-CCC

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

4 Repeat

7 Repeat

2 Repeat

DRD411p

.

H u m a n DH u m a n D 44 G e n e P C RG e n e P C R

A D H D F a m i l i e sA D H D F a m i l i e s

P r i m e r S e t . 4 : H DP r i m e r S e t . 4 : H D 44 -- 2 9 2 6 / H D2 9 2 6 / H D 44 -- 3 6 1 0 R3 6 1 0 R

D R DD R D 44 -- E x o n I I IE x o n I I I

b pb p 11 22 33 44 55 66 77 88 99 1 01 0 1 11 1 1 21 2 1 31 3 1 41 4

G 0 0 0 1 0G 0 0 0 1 0 G 0 0 0 2 9G 0 0 0 2 9 G 0 0 0 4 8G 0 0 0 4 8

10

01

00 -- b

p D

NA

la

dd

er

bp

DN

A l

ad

de

r

F a m i l y C o d eF a m i l y C o d e

9 0 09 0 08 0 08 0 07 0 07 0 0

6 0 06 0 0

5 0 05 0 0

1 , 0 0 01 , 0 0 0

1 , 2 0 01 , 2 0 0

4 0 04 0 0

L a n e s 1 L a n e s 1 - -- - G 0 0 0 1 0 . Y D 0 2 6 G 0 0 0 1 0 . Y D 0 2 6 - -- - S i s t e rS i s t e rL a n e s 2 L a n e s 2 - -- - G 0 0 0 1 0 . Y D 0 3 2 G 0 0 0 1 0 . Y D 0 3 2 - -- - F a t h e rF a t h e rL a n e s 3 L a n e s 3 - -- - G 0 0 0 1 0 . Y D 0 2 9 G 0 0 0 1 0 . Y D 0 2 9 - -- - T w i n S i s t e rT w i n S i s t e rL a n e s 4 L a n e s 4 - -- - G 0 0 0 1 0 . Y D 0 3 0 G 0 0 0 1 0 . Y D 0 3 0 - -- - B r o t h e rB r o t h e r

L a n e s 6 L a n e s 6 - -- - G 0 0 0 1 0 . Y D 0 3 1 G 0 0 0 1 0 . Y D 0 3 1 - -- - P r o b a n dP r o b a n d

L a n e s 7 L a n e s 7 - -- - G 0 0 0 2 9 . Y D 0 0 7 G 0 0 0 2 9 . Y D 0 0 7 - -- - S i s t e rS i s t e r

L a n e s 5 L a n e s 5 - -- - G 0 0 0 1 0 . Y D 0 3 3 G 0 0 0 1 0 . Y D 0 3 3 - -- - M o t h e rM o t h e r

L a n e s 8 L a n e s 8 - -- - G 0 0 0 2 9 . Y D 0 0 9 G 0 0 0 2 9 . Y D 0 0 9 - -- - B r o t h e rB r o t h e rL a n e s 9 L a n e s 9 - -- - G 0 0 0 2 9 . Y D 0 0 8 G 0 0 0 2 9 . Y D 0 0 8 - -- - F a t h e rF a t h e rL a n e s 1 0 L a n e s 1 0 - -- - G 0 0 0 2 9 . Y D 0 1 0 G 0 0 0 2 9 . Y D 0 1 0 - -- - P r o b a n dP r o b a n d

L a n e s 1 1 L a n e s 1 1 - -- - G 0 0 0 4 8 . Y D 0 2 5 G 0 0 0 4 8 . Y D 0 2 5 - -- - P r o b a n d ( L N C G )P r o b a n d ( L N C G )

L a n e s 1 3 L a n e s 1 3 - -- - G 0 0 0 4 8 . Y D 0 2 3 G 0 0 0 4 8 . Y D 0 2 3 - -- - F a t h e rF a t h e r

L a n e s 1 4 A 2 2 6 2L a n e s 1 4 A 2 2 6 2

L a n e s 1 2 L a n e s 1 2 - -- - G 0 0 0 4 8 . Y D 0 2 4 G 0 0 0 4 8 . Y D 0 2 4 - -- - M o t h e rM o t h e r

Gel-based allele length

Nucleotide sequence

48 bp VNTR (imperfect repeat)CCC-GCG-CCC-CGC-CTC-CCC-CAG-GAC-CCC-TGC-GGC-CCC-GAC-TGT-GCG-CCC

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

CCCGCGCCCGGCCTTCCCCGGGGTCCCTGCGGCCCCGACTGTGCGCCC

2CCCGCGCCCGGCCTCCCCCCGGACCCCTGCGGCTCCAACTGTGCTCCC

3GCCGCGCCCAGCCTCCCCCAGGACCCCTGTGGCCCCGACTGTGCGCCC

4CCCGCGCCCCGCCTCCCCCAGGACCCCTGCGGCCCCGACTGTGCGCCC

1

Nucleotide Variation Across Repeats(Lichter, Barr, Kennedy et al, 1993)

10 20 30 40 48() 1 A CCC GCG CCC CGC CTC CCC CAG GAC CCC TGC GGC CCC GAC TGT GCG CC

Pro Ala Pro Arg Leu Pro Gln Asp Pro Cys Gly Pro Asp Cys Ala Pro () 2 C ... ... ... G.. ..T ... .G. .GT ... ... ... ... ... ... ... ..

Gly Arg Gly () 3 C G.. ... ... A.. ... ... ... ... ... ..T ... ... ... ... ... ..

Ala Ser () 4 C ... ... ... G.. ... ... .C. ... ... ... ... T.. A.. ... ..T ..

Gly Pro Ser Asn () 5 C ... ... ... G.. ... ... ... ... ... ... ... ... ... ... ... ..

Gly () 6 C G.. ... ... G.. ... ... .C. ... ... ... ... ... ... ... ... ..

Ala Gly Pro () 7 C ... ... ... G.. ..T ... ... ... ... ..T ... ... ... ... ... ..

Gly 

New Sequence Variants (1)

20 C G.. ... ... G.. ... ... .C. ... ... ... ... T.. A.. ... ..T .. Ala Gly Pro Ser Asn 21 C G.. ... ... A.. ... ... ... ... ... ... ... T.. A.. ... ..T .. Ala Ser Ser Asn 22 C G.. ... ... G.. ... ... ... ... ... ... ... T.. A.. ... ..T .. Ala Gly Ser Asn 23 C ... ... ... G.. ... ... ... ... ... ..T ... ... ... ... ... .. Gly 24 . ... ... ... G.. ..T ... .G. .GT ... ... ... ... ... ... ... .. Gly Arg Gly 25 C G.. ... ... A.. ... ... .C. ... ... ... ... ... ... ... ... .. Ala Ser Pro 26 C ... ... ... G.. ..T ... .G. .TT ... ... ... ... ... ... ... .. Gly Arg Val 27 C ... ... ... G.. ... ... .C. ... ... ... ... ... ... ... ... .. Gly Pro 

Asymmetric Crossover of Two 4R ALLELES

• Combinations of “motifs” define nucleotides in the sequence of an allele • Most nucleotide sequences are based on the 4R allele (motifs 1-2-3-4)• Recombination of two 4R alleles can produce a 2R allele

1-2-3-4

1-2-3-4

2R-ALLELE

1-2-3-4

1-4

1-2-3-4

1-2-3-4

6R-ALLELE

1-2-3-4

1-2-3-2-3-4

Variation in the 48 base-pair repeat “motif”

MOTIF SEQUENCE

A CCC GCG CCC CGC CTC CCC CAG GAC CCC TGC GGC CCC GAC TGT GCG CC Pro Ala Pro Arg Leu Pro Gln Asp Pro Cys Gly Pro Asp Cys Ala Pro

C G.. ... ... A.. ... ... ... ... ... ..T ... ... ... ... ... ..

Ala Ser

C ... ... ... G.. ... ... .C. ... ... ... ... T.. A.. ... ..T ..

Gly Pro Ser Asn

C G.. ... ... A.. ... ... ...

Ala Ser

... ... ... ... T.. A.. ... ..T ..

Ser Asn

21

UCI-CDC Studies of DRD4 & Molecular Genetics of ADHD

• Ding, Chi, Grady et al, 2002• Swanson, Moyzis et al, 2002• Fosella, Sommer, Fan et al, 2002• Goldsmith, Crabbe, Dawson et al, 2003• Grady, Chi, Ding et al, 2003• Wang, Ding et al, 2004• Cornish, Manly, Savage et al, 2005• Leung, Lee et al, 2005• Stevenson, Asherson et al, 2005• Feng, Crosbie et al, 2005• Grady, Hakxhi et al, 2005 • Preston, Kollins, Swanson et al, 2005

Exon 3 Sequences for 36 DRD4 Alleles

Ding et al., PNAS, 2002, 99, 309-314“Evidence of Positive Selection Acting at the

Humand Dopamine Receptor D4 Gene Locus”

Haplotypes of 600 DRD4 Exon 3 Alleles Allele F N Haplotype Allele F N Haplotype2R .088 55 6R .022 24

43 1-4 16 1-2-3-2-3-4 12 30-4 * 2 1-2-6-5-2-20

3R .024 36 2 1-2-6-5-2-416 1-7-4 1 1-2-14-17-2-49 1-2-4 1 1-6-5-2-5-44 1-11-33 * 1 1-2-13-2-5-193 1-9-4 1 24-6-5-2-5-41 1-2-22 7R .192 1991 1-2-21 177 1-2-6-5-2-5-4

1 1-2-31 5 1-2-6-5-2-5-19 *1 1-2-32 3 1-2-6-5-2-3-4

4R .651 250 3 1-2-6-5-13-5-4 *238 1-2-3-4 2 1-8-25-5-2-5-43 1-2-14-4 2 1-2-3-5-2-5-42 1-2-13-4 1 1-2-6-5-2-13-42 1-2-12-4 1 1-2-29-17-2-5-41 1-17-3-4 1 1-2-6-2-2-5-41 1-9-12-4 1 1-8-25-5-2-3-41 1-8-3-4 1 1-2-6-16-2-3-41 1-10-3-4 1 1-2-6-5-2-14-41 1-9-3-4 1 1-2-3-17-2-5-4

5R .016 27 8R .006 612 1-3-2-3-4 * 2 1-2-6-5-17-2-13-35 *4 1-2-13-34-4 * 1 1-2-6-5-2-2-5-43 1-2-2-3-4 1 1-2-6-26-5-26-3-352 1-2-6-5-4 1 1-2-6-26-5-26-3-42 1-11-2-3-4 1 1-2-6-18-5-18-3-41 1-3-2-14-4 1 1-2-6-23-4 9R <.001 1 1-8-25-5-2-5-2-23-41 1-2-3-9-4 10R <.001 1 1-2-15-6-2-6-5-2-5-41 1-2-3-27-4 11R <.001 1 1-2-3-27-5-23-25-5-2-

5-28 F: observed allele frequency in 2836 chromosomes from 37 worldwide human populations. (Chang et al, 1996)N: allele number identified by sequence analysis in this study; non-4R alleles were oversampled by 2-3 fold. Alleles with adjacent asterisks indicate common variants found only in a single population sample (2R 30-4, surui; 3R 1-11-33, nasioi; 5R 1-3-2-3-4, chinese; 5R 1-2-13-34-4, biaka; 7R 1-2-6-5-2-5-19, surui; 7R 1-2-6-5-13-5-4, nasioi; 8R 1-2-6-5-17-2-13-35, biaka). Alleles with a single representation were, by definition, found in only one population.

 

4R-ALLELE

1-2-3-4

1-2-3-4

5R-ALLELE1-2-2-3-4

1-2-3-4

1-2-3-4

3R-ALLELE

1-2-3-4

1-7-4

1-2-3-4

MultipleMutations/GeneConversions

L LL LS SS S

G - GG - G

2R-ALLELE

1-2-3-4

1-4

1-2-3-4

L LL LS SS S

A - CA - CG - GG - G

A - CA - C

6R-ALLELE

1-2-3-4

1-2-3-2-3-4

7R-ALLELE

1-2-6-5-2-5-4L LL L A-CA-C

DRD4 Gene with 70 SNPs for 103

Individuals

11 70

103

(51)

(43)

(9)

Ding et al., 2002, PNAS, 99:309-314 • The 2R to 6R-alleles can be explained by one-step unequal

recombination events between 4R alleles.

• The formation of the 7R allele would require >1 recombination and multiple (>6) mutations.

• Intraallelic variability est. of allele age indicate that the 7R-allele is 10 fold “younger” than the 4R allele.

• Allelic variability of 4R (but not 7R) alleles in African DNA is greater than from other sources.

MIGRATION PATHS “OUT OF AFRICA” INTO NEW WORLD(Chen et al., 1999, Evolution and Human Behavior, 20:309-324)

P(7R) = .63

P(7R) = .26

P(7R) = .15

CBS 60 Minutes, 12/5/04ATTENTION DEFICIT DISORDER

GROWS UP

David Neeleman

David Neeleman says he always knew his brain worked a little differently from the rest.

"I scored so low on the English portion of the ACT test that my counselor hauled me in and said, 'David, had you just answered 'C' on every question, you would've done better. You would've done 30 percent better than what you did,'” says Neeleman.

He spent years in various jobs, in a sort of limbo, before he realized he had a clear-cut case of ADD. Even so, he’s a huge success. He's CEO of Jet Blue, the low-cost, no-frills carrier that has shaken up the airline industry.

David Neeleman

Neeleman says many of his out-of-the-box ideas are thanks to his ADD. "In the midst of all the chaos in your mind, and all of the disorganization, and all the trouble getting started, and procrastination, your brain just thinks a little bit differently," he says. "And you can come up with things."

Ideas like e-tickets, or ticketless travel, which is perfect for someone who is always losing things, and live TV, is making a his company profit while most of the airline industry is in trouble. But having finally discovered he had a certifiable medical condition, Neeleman decided to do absolutely nothing about it.

David NeelemanHe says that many ADD sufferers are attracted to high-risk or entrepreneurial careers. And his list of people he thinks may have ADD include Bill Clinton, and Richard Branson.

There’s also speculation that some great figures in history had ADD and led tortured but productive lives -- Leonardo Da Vinci, Pablo Picasso, Winston Churchill. And, ADD websites claim that Thomas Edison had ADD, which leads one to wonder if Edison had been on medication, he might have invented the pogo stick instead of the light bulb.

"The idea of treatment isn't to confine people and take away their creativity," says Adler. "It's really to try to help them be more productive and tap into their creativity."

Neuropsychology Review, 2007

Two Presumed Etiologies

• Environmental– Preterm birth– Smoking during pregnancy

• Genetic– Dopamine genes (DRD4 and DAT)– Genome scan

National Children’s Study (NCS) • Study of environmental influences on children's health

• Longitudinal cohort study birth to 21 years

• National in scope in 96 representative counties

• Enrollment during or before pregnancy

• Large sample size (100,000 live births)

• Exposure broadly defined (physical, chemical, biological, and psychosocial)

• Outcome broadly defined (priorities: pregnancy-related; injury; asthma; obesity, diabetes, physical development; child development and mental health)

• Evaluation of gene-environment interactions