BEHAVIORAL GENETICS: Theory, Substance & Methods · BEHAVIORAL GENETICS: Theory, Substance &...

BEHAVIORAL GENETICS:Theory, Substance & Methods

Michael Stallings, Ph.D.

Institute for Behavioral GeneticsUniversity of Colorado

Behavioral GeneticsBehavioral Genetics

Quantitative Genetic StudiesQuantitative Genetic Studies

Gene Mapping StudiesGene Mapping StudiesLinkage StudiesLinkage StudiesAssociation StudiesAssociation Studies

Quantitative GeneticsQuantitative GeneticsExperimental animal studiesExperimental animal studiesTwin, adoption, and family studiesTwin, adoption, and family studies

How can we use these tools to quantify How can we use these tools to quantify the extent to which genetic and the extent to which genetic and environmental factors contribute to environmental factors contribute to individual differences in behavior?individual differences in behavior?

Understanding Individual Differences

Observed phenotypic variance = individual differences

Primary GoalsPrimary Goals

Decompose observed phenotypic variation Decompose observed phenotypic variation into genetic and environmental sources, or into genetic and environmental sources, or variance componentsvariance componentsDo these influences operate similarly, or Do these influences operate similarly, or differently, differently,

-- for males and femalesfor males and females-- across developmental stagesacross developmental stages-- in different contextsin different contexts

Why do we think genes influence Why do we think genes influence behavior?behavior?

Animal models: selection, strain differences, Animal models: selection, strain differences, crosscross--breeding, gene manipulations, e.g. breeding, gene manipulations, e.g. knock outsknock outsInherited disordersInherited disordersPatterns of family resemblance, e.g. twin Patterns of family resemblance, e.g. twin studies, adoption studies, family studiesstudies, adoption studies, family studiesLinkage and association studiesLinkage and association studies

Inbreed Within High and Low Responders

Observed sleep time at each generation

Top 10%

Long Sleep

Bottom 10%

Short Sleep

DeFries et al, 1978

ParentParent--offspring correlations between first principal component offspring correlations between first principal component scores derived from tests of specific cognitive abilities (scores derived from tests of specific cognitive abilities (PlominPlomin et et

al., 1997)al., 1997)

-0.1

0

0.1

0.2

0.3

0.4

0 2 4 6 8 10 12 14 16 18Age of Child

Ave

raged P

are

nt-

Offsp

ring

Corr

ela

tions

BiologicalAdoptiveControl

Monozygotic (MZ) and dizygotic (DZ) twin Monozygotic (MZ) and dizygotic (DZ) twin correlations for individual IQ scores in the correlations for individual IQ scores in the

Colorado Longitudinal Twin StudyColorado Longitudinal Twin Study(Data from: Bishop et al, 2003, (Data from: Bishop et al, 2003, IntelligenceIntelligence ; Friedman et al, 2006, ; Friedman et al, 2006, Psychological Science)Psychological Science)

0

0.2

0.4

0.6

0.8

1

1 3 5 7 9 11 13 15

Age of assessment (years)

Corr

elat

ion

MZDZ

Twin studies of common Twin studies of common phenotypesphenotypes

PhenotypePhenotype rMZrMZ rDZrDZ

BMI (age 20 yrs)BMI (age 20 yrs) .80.80 .42.42 [[FabsitzFabsitz et al, 1992]et al, 1992]IQ (age 7 years)IQ (age 7 years) .76.76 .40.40 [Bishop et al, 2001][Bishop et al, 2001]IQ (age 16 years)IQ (age 16 years) .84.84 .41.41 [Friedman et al, 2006][Friedman et al, 2006]Any drug, ever useAny drug, ever use .82.82 .75.75 [Rhee et al, 2003][Rhee et al, 2003]Any drug, problem useAny drug, problem use .82.82 .46.46 [Rhee et al, 2003][Rhee et al, 2003]Depression (Finns, female)Depression (Finns, female) .43.43 .16.16 [[WamboldtWamboldt et al, 2000]et al, 2000]AtopyAtopy (Finns, female)(Finns, female) .30.30 .15.15 [[WamboldtWamboldt et al, 2000]et al, 2000]Heart rate, resting (age 7)Heart rate, resting (age 7) .65.65 .44.44 [[VanHulleVanHulle et al, 2000]et al, 2000]HDL cholesterol (14 years)HDL cholesterol (14 years) .81.81 .21.21 [Nance et al, 1998][Nance et al, 1998]Neuroticism (Neuroticism (females, Australiafemales, Australia) ) .42.42 .17.17 [Keller et al, 2005][Keller et al, 2005]Extraversion (Extraversion (females, Australiafemales, Australia) ) .46.46 .18.18 [Keller et al, 2005][Keller et al, 2005]

Twin studies of common Twin studies of common phenotypesphenotypes

PhenotypePhenotype GeneticGenetic EnvironmentalEnvironmentalShared NonShared Non--sharedshared

BMI (age 20 yrs)BMI (age 20 yrs) .76.76 .04.04 .20 .20 IQ (age 7 years)IQ (age 7 years) .72.72 .04.04 .24.24IQ (age 16 years) IQ (age 16 years) .82.82 .00.00 .18.18Any drug, ever useAny drug, ever use .14.14 .68.68 .18.18Any drug, problem useAny drug, problem use .72.72 .10.10 .18.18Depression (Finns, female)Depression (Finns, female) .43.43 ------ .57.57AtopyAtopy (Finns, female)(Finns, female) .30.30 .00.00 .70.70Heart rate, resting (age 7)Heart rate, resting (age 7) .42.42 .23.23 .35.35HDL cholesterol (14 years)HDL cholesterol (14 years) .81.81 ------ .19.19Neuroticism (Neuroticism (females, Australiafemales, Australia) ) .42.42 ------ .58.58Extraversion (Extraversion (females, Australiafemales, Australia) ) .46.46 ------ .54.54

Important Caveat About Important Caveat About HeritabilityHeritability

Heritability is Heritability is notnot an absolute property of an absolute property of a physical or behavioral characteristic. a physical or behavioral characteristic.

It is a function of the genetic and It is a function of the genetic and environmental variation environmental variation for a given for a given population in particular circumstances, population in particular circumstances, and at a particular developmental stage.and at a particular developmental stage.

Elaborations of the simple model:Elaborations of the simple model:

sexsex--limitationlimitationGG--E correlationE correlationGxEGxE interactioninteractionassortativeassortative matingmatingnonnon--additive genetic variationadditive genetic variationsocial interactionsocial interactionobserver effectsobserver effectspleiotropypleiotropypatterns of developmentpatterns of developmentmeasured environmentsmeasured environmentsmeasured genesmeasured genes

ParentParent--offspring correlations between first principal component offspring correlations between first principal component scores derived from tests of specific cognitive abilities (scores derived from tests of specific cognitive abilities (PlominPlomin et et

al., 1997)al., 1997)

-0.1

0

0.1

0.2

0.3

0.4

0 2 4 6 8 10 12 14 16 18Age of Child

Ave

raged P

are

nt-

Offsp

ring

Corr

ela

tions

BiologicalAdoptiveControl

Monozygotic (MZ) and dizygotic (DZ) twin Monozygotic (MZ) and dizygotic (DZ) twin correlations for individual IQ scores in the correlations for individual IQ scores in the

Colorado Longitudinal Twin StudyColorado Longitudinal Twin Study(Data from: Bishop et al, 2003, (Data from: Bishop et al, 2003, IntelligenceIntelligence ; Friedman et al, 2006, ; Friedman et al, 2006, Psychological Science)Psychological Science)

0

0.2

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1 3 5 7 9 11 13 15

Age of assessment (years)

Corr

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MZDZ

Human twin, family, and adoption studies Human twin, family, and adoption studies of substance use/abuse/dependenceof substance use/abuse/dependence

Rhee, Hewitt, Young, Corley, Crowley, & Stallings (2003) Genetic and environmental influences on substance initiation, use, and problem use in adolescents. Arch Gen Psychiatry. 60:1256-1264

Young, Corley, Stallings, Rhee, Crowley, Hewitt (2002) Substance use, abuse and dependence in adolescence: prevalence, symptom profiles and correlates. Drug Alcohol Depend. 68: 309-22.

Percentage of community sample adolescents Percentage of community sample adolescents experimenting with substancesexperimenting with substances

01020304050607080

12 13 14 15 16 17 18Age in years

Perc

ent

alcohol,malesalcohol,femalestobacco,malestobacco,femalesmarijuana,malesmarijuana,females`other',males`other',females

Percentage of community sample adolescents Percentage of community sample adolescents dependent on substancesdependent on substances

0

5

10

15

20

25

12 13 14 15 16 17 18Age in years

Perc

ent

alcohol, males

alcohol, females

tobacco, males

tobacco, females

marijuana, males

marijuana, females

`other', males

`other', females

any substance, males

any substance, females

Substance use and the development of dependence Substance use and the development of dependence symptoms are common in adolescence. symptoms are common in adolescence.

By age eighteen, 70% of adolescents are experimenting By age eighteen, 70% of adolescents are experimenting with alcohol, 1 in 3 with marijuana, 1 in 3 with tobacco, 1 with alcohol, 1 in 3 with marijuana, 1 in 3 with tobacco, 1 in 10 with other illicit drugs. 1 in 5 show dependence on in 10 with other illicit drugs. 1 in 5 show dependence on some substance (often nicotine).some substance (often nicotine).

There are few marked sex differences in substance use There are few marked sex differences in substance use or dependence during adolescence.or dependence during adolescence.

There is a marked, almost linear, increase in substance There is a marked, almost linear, increase in substance use and then dependence during the high school yearsuse and then dependence during the high school years. .

Family resemblance for `any drug’ in the Family resemblance for `any drug’ in the Colorado Drug Research CenterColorado Drug Research Center

(Rhee et al, Arch. General (Rhee et al, Arch. General PsychiatPsychiat., 2003)., 2003)

00.10.20.30.40.50.60.70.80.9

Use Problem use

Behavior

Corr

elat

ion MZ twins

DZ twinsFull SiblingsAdoptive Siblings

All aspects of substance use show family All aspects of substance use show family similarity.similarity.

Much of the family similarity appears to Much of the family similarity appears to be genetic, especially for abuse and be genetic, especially for abuse and dependence.dependence.

The shared environmental influences are The shared environmental influences are more marked for close age siblings, more marked for close age siblings, underscoring the likely importance of underscoring the likely importance of peer influences.peer influences.

Problem Substance UseProblem Substance Use

Comorbidity and genetic Comorbidity and genetic pleiotropypleiotropy

Are there common risk factors across Are there common risk factors across different substances of abuse?different substances of abuse?

To what extent is substance dependence To what extent is substance dependence comorbid with other psychiatric comorbid with other psychiatric symptoms?symptoms?

To what extent are comorbidity or To what extent are comorbidity or correlations among traits due to correlations among traits due to common genetic influences?common genetic influences?

MulitivariateMulitivariate Genetic AnalysisGenetic Analysis

Univariate AnalysisUnivariate Analysis

P

G E

Square = observed phenotype/trait

Circles = latent influences


P

G C E

C = common, or shared environment

E = unique, or nonshared environment


P

C EA D

A = additive genetic influences

D = nonadditive (dominant) genetic influences

Multivariate AnalysisMultivariate Analysis

P1

E1 E2

A1 A2

P2

Multivariate AnalysisMultivariate Analysis

P1

E1 E2

A1 A2

P2

rA

rE

Genetic and Environmental Vulnerabilities Underlying Adolescent Genetic and Environmental Vulnerabilities Underlying Adolescent Substance Use and Problem Use (Young et al., 2006)Substance Use and Problem Use (Young et al., 2006)

ALCTOB MAR TOB ALC MAR

AT AC AM TT TA TM

EMEAETCMCACT

Substance Use: repeated use as defined by CIDI-SAM

.68 .66.23

.38.46.34

.15

.31

.14

.09 .16

.09

.34

.39.55 .52

.52.68

.33.22

.17

.14.20

.21

Note the substantial shared environmental influences on Note the substantial shared environmental influences on substance use,substance use,both specific to twins (tboth specific to twins (t22) and for non) and for non--twin siblings (ctwin siblings (c22))


TT TA TM

CMCACT

.34

.39.55 .52

.52.68

.33.22

.17

.14.20

.21

And relatively And relatively modestmodest intercorrelationsintercorrelations among the genetic and among the genetic and environmental influences for measures of environmental influences for measures of substance usesubstance use


AT AC AM TT TA TM

EMEAETCMCACT

.15

.31

.14

.09 .16

.09

.33.22

.17

.14.20

.21


AT AC AM TT TA TM

EMEAETCMCACT

Problem Use: endorsement of 1+ DSM dependence criteria

.73 .80.84

.43.49.36

.60

.56

.62

.07 .09

.06

.36

.32.45 .08

.26.23

.21

Correlations among substance dependence Correlations among substance dependence symptoms and other psychiatric symptoms in symptoms and other psychiatric symptoms in

our adolescent community sampleour adolescent community sample

0.430.430.230.230.230.230.110.11DependenceDependenceVulnerabilityVulnerability

0.290.290.170.170.100.100.070.07OtherOther

0.390.390.210.210.170.170.070.07MarijuanaMarijuana

0.360.360.200.200.200.200.120.12AlcoholAlcohol

0.370.370.220.220.210.210.060.06NicotineNicotine

ConductConductDisorderDisorder

ADHDADHDMDDMDDGADGAD

Other Structural ModelsOther Structural Models

ASB ALC DRG

A1 A2 A3

CholeskyCholesky DecompositionDecomposition

ASB ALC DRG

A1 A2 A3

Common Factor ModelCommon Factor Model

ASB ALC DRG

A C E

LT

Button et al., 2007 Button et al., 2007 (Drug & Alcohol Dependence)(Drug & Alcohol Dependence)

ALC DRG

A1 A2

.83.73

.00

E1 E2

.56.20

.46


ASB ALC DRG

A1 A2 A3

.76

.76

.51


ASB ALC DRG

A1 A2 A3

.76

.76

.51.63

.37

.00

Substance Abuse is Part of a Spectrum Substance Abuse is Part of a Spectrum of Problem Behaviorsof Problem Behaviors (Young et al., 2000)(Young et al., 2000)

BehDisinhib

A E

CD SUB ADHD NS

.92 .40

.47.40 .68

.47

There is marked comorbidity both across There is marked comorbidity both across substances and between substance use substances and between substance use and other psychiatric problems, especially and other psychiatric problems, especially externalizing problem behavior, such as externalizing problem behavior, such as conduct disorder.conduct disorder.

In adolescence, underlying genetic In adolescence, underlying genetic factors may have general influences on factors may have general influences on vulnerability to substance use and vulnerability to substance use and dependence and, possibly, conduct dependence and, possibly, conduct problems.problems.

GeneGene--EnvironmentEnvironmentInteractionInteraction

Science. 2002 Aug 2;297(5582):851Science. 2002 Aug 2;297(5582):851--4. 4.

Role of genotype in the cycle of Role of genotype in the cycle of violence in maltreated children.violence in maltreated children.

CaspiCaspi A, A, McClayMcClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, A, PoultonPoulton R.R.

Medical Research Council Social, Genetic, and Developmental Medical Research Council Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's CollPsychiatry Research Centre, Institute of Psychiatry, King's College, ege, London SE5 8AF, UK.London SE5 8AF, UK.

““the the CaspiCaspi hypothesis….”hypothesis….”

Caspi et al., Science, 297: 851-854

HaberstickHaberstick, , LessemLessem, , HopferHopfer, , SmolenSmolen, , EhringerEhringer, Timberlake, Hewitt (2005) Monoamine , Timberlake, Hewitt (2005) Monoamine oxidaseoxidase A A (MAOA) and antisocial behaviors in the presence of childhood and(MAOA) and antisocial behaviors in the presence of childhood and adolescent maltreatment. adolescent maltreatment. American Journal of Medical Genetics Part B: American Journal of Medical Genetics Part B: NeuropsychiatricNeuropsychiatric Genetics, Genetics, 135: 59135: 59--6464

Huizinga et al, Biological Psychiatry 2005

Foley et al, Archives of General Psychiatry,2004

0102030405060708090

100

0 1 2 3 4

Level of exposure to childhood adversity

Pe

rce

nt

wit

h

Co

nd

uct

D

iso

rde

r

Low MAO-AHigh MAO-A

Foley et al, 2004

0102030405060708090

100

0 1 2 3 4


Pe

rce

nt

wit

h

Co

nd

uct

Dis

ord

er

Low MAO-AHigh MAO-A

N = 1

Foley et al, 2004changing two cases

0102030405060708090

100

0 1 2 3 4


Pe

rce

nt

wit

h

Co

nd

uct

D

iso

rde

r

Low MAO-AHigh MAO-A

Foley et al, 2004binning adversity to have >5

subjects per cell

0102030405060708090

100

0 1 2+


Pe

rce

nt

wit

h

Co

nd

uct

D

iso

rde

r

Low MAO-AHigh MAO-A

Young et al, American Journal of Psychiatry, 2006Young et al, American Journal of Psychiatry, 2006

Genotype × Environment InteractionGenotype × Environment Interactionin Psychopathology: Fact or Artifact?in Psychopathology: Fact or Artifact?LindonLindon J. Eaves, Twin Research, 2006J. Eaves, Twin Research, 2006

``The main outcome of this study was simulated``The main outcome of this study was simulatedliabilities and diagnoses of major depression andliabilities and diagnoses of major depression and

antisocial behavior. Analysis of the dichotomized dataantisocial behavior. Analysis of the dichotomized databy logistic regression frequently detected significantby logistic regression frequently detected significantG × E interaction even though none was present forG × E interaction even though none was present for

liability. There is therefore reason to question the liability. There is therefore reason to question the biological significance of published findings.’’biological significance of published findings.’’

Behavior genetic studies suggest that Behavior genetic studies suggest that bothbothgenetic and environmental influences are genetic and environmental influences are ubiquitous.ubiquitous.Gene by environment interactions are a Gene by environment interactions are a given given ------ heritability may be different in heritability may be different in different environments, at different ages, different environments, at different ages, at different stages of development.at different stages of development.Genes can create both stability and Genes can create both stability and change during development.change during development.Genes often influence multiple aspects of Genes often influence multiple aspects of behavior (behavior (pleiotropypleiotropy).).

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