bottom(s) up! a biological approach to behavioral genetics

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?