bottom(s) up! a biological approach to behavioral genetics
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Bottom(s) Up! A biological approach to behavioral genetics. Two Approaches to Human Genetics. Melancholia. 2009. The Wellcome Trust Case Control Consortium Is Behavior Different?. 14,000 Cases 3,000 Controls. WGA’s of Schizophrenia. MCH: major histocompatibility complex HIST1H2BJ: histone - PowerPoint PPT PresentationTRANSCRIPT
Bottom(s) Up!A biological approach to behavioral genetics
Clinical Disorders A B C
Genes
Molecular Phenotypes
Behavioral Phenotypes
Neural Phenotypes
Two Approaches to Human Genetics
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Melancholia
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2009
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The Wellcome Trust Case Control ConsortiumIs Behavior Different?
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14,000 Cases3,000 Controls
WGA’s of Schizophrenia
MCH: major histocompatibility complex
HIST1H2BJ: histone
PRSS16: serineprotease 16
PGBD1: piggyBac transposable element derived 1
NOTCH4: notch4
NRGN: neurogranin
TCF4: transcription factor 4
Many SNP’s of Small Effect Size Contribute to Risk for SCZ
n = 8,537 16,124 23,563 31,029 37,655
Power in Association Studies
Make the Effect Large
Clinical Disorders A B C
Genes
Molecular Phenotypes
Behavioral Phenotypes
Neural Phenotypes
Clinical Disorders A B C
Genes
(Comprised of multiplebiological subtypes)
Focus on Anorexia Nervosa
• Defined by diet restriction - weight <85% ideal BMI• female risk >>> male risk• Onset during adolescence• High comorbidity with anxiety disorders• Accompanied by obsessive, rigid, perfectionistic personality traits• Strong resistance to re-feeding (food phobia)• SSRI’s not effective in underweight state, can prevent relapse and
treat anxiety/personality traits.
Fear learning model of Anorexia Nervosa
AnxietyHarm AvoidanceObsessivenessPerfectionism
Female gender
Adolescence
Dietrestriction
SSRI Rx
ReducedAnxiety
Refeeding
Crusty personality
Focus on the Serotonin Transporter
Messenger RNA produced from the SERT gene is processed into two forms:
SERT PROTEIN RISK PROTECTIVE * *
T/G
SERT PROTEIN RISK PROTECTIVE * *
T/G
AAAAAAAA
AAAAAAA
rs3813034~0.45 in Caucasians
Gender difference in vs. Forms of SERT
0.8
1
1.2
1.4
1.6
HUMAN MOUSE
normalized DPF
male
female*
*
rs3813034 genotype influences vs. forms of SERT
0.8
1
1.2
1.4
1.6
1.8
2
GG GT TT
LB
Brain
*
**
vs. Forms of SERTVary Across Development
0.88
0.92
0.96
1
1.04
1.08
P20 P35 P60
normalized DPF
*
*
SSRI’s Increases the vs. Form of SERT
0.9
0.95
1
1.05
1.1
1.15
1.2
control fluoxetine
normalized DPF
*
60% Diet Restriction as a Model of Anorexia Nervosa
60% by weight60% by weight
Diet Restriction induces the vs. Form of SERT
0.96
1
1.04
1.08
1.12
control 60%
normalized DPF
Revisiting the vs. Forms of SERTin the Fear Learning Model of Anorexia Nervosa
AnxietyHarm AvoidanceObsessivenessPerfectionism
Female gender
Adolescence
Dietrestriction
SSRI Rx
ReducedAnxiety
Refeeding
Crusty personality
Risk alleles of rs3813034
60% by weight
AnxietyHarm AvoidanceObsessivenessPerfectionism
Female gender
Adolescence
Diet restriction
SSRI Rx
ReducedAnxiety
Refeeding
Crusty personality
Risk alleles of rs3813034