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. Phenotypic Effects of Individual Polymorphisms are small. WGA’s of Schizophrenia. MCH: major histocompatibility complex HIST1H2BJ: histone PRSS16: serineprotease 16 - 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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Phenotypic Effects of Individual Polymorphisms are small
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)
Structural Neuroimaging - The New Phrenology?
Radioligand Imaging Identifies Neurochemical Effects
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fMRI Identifies Neurobehavioral Effects
Functional Connectivity Analysis Identifies Affected Circuits
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Multiple Testing on the Phenotype Side
L Homozygotes > S Carriers L Homozygotes < S Carriers
Meta-Analysis of 5HTTLPR and Amygdala Activation
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Vertical Approach Refines Hypotheses
Clinical Disorders A B C
Genes
Molecular Phenotypes
Behavioral Phenotypes
Neural Phenotypes
Focus on the Serotonin Transporter
Polyadenylation Polymorphism in SERT
rs3813034
Yes, rs3813034 Has a Molecular Phenotype
What Else Do We Know About the SERT DPF?
Anything Else?
0
0.4
0.8
1.2
1.6
brain region
distal polyadenylation fraction
raphe
amygdala
cortex
That Sounds Like the Circuitry of theEmotional Go/NoGo Task
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And Males Habituate Better Than Females in the Emotional Go/NoGo
Can We Use All This Information to Develop a Model of rs3813034 Effects on Performance in
the Emo Go/NoGo?
OFC
RN
• Res p onse
L at e nc y
• T rait Anx i et y
A
Amygdala
T Allele/↑DPF
OFC
RN
• Res p onse
L at e nc y
• T rait Anx i et y
B
Amygdala
G Allele/↓DPF
• Respons e latency • Trait Anxiety
• Respons e latency • Trait Anxiety
Does the Model Work?
Counts PercentGenotype
GG GT TT Total GG GT TTAll Control 112 250 182 544 0.21 0.46 0.34 Chi-Sq= 10.03
Case 80 155 72 307 0.26 0.50 0.24 p= 0.007
Females Control 51 126 93 270 0.19 0.47 0.34 Chi-Sq= 8.93Case 64 124 57 245 0.26 0.51 0.23 p= 0.012
Males Control 61 124 89 544 0.22 0.45 0.32 Chi-Sq= 1.65Case 16 31 15 307 0.26 0.50 0.24 p= 0.439
Allele G T G T Odds RatioAll Control 474 614 0.44 0.56 Chi-Sq= 9.45 1.36
Case 315 299 0.51 0.49 p= 0.002 (1.12-1.66)
Females Control 228 312 0.42 0.58 Chi-Sq= 8.75 1.45Case 252 238 0.51 0.49 p= 0.003 (1.13-1.85)
Males Control 246 302 0.45 0.55 Chi-Sq= 1.42 1.27Case 63 61 0.51 0.49 p= 0.233 (0.86-1.87)
Table 1. Association of rs3813034 and panic disorder
Association of rs3813034 and Panic Disorder
What About Disease?