19 th international workshop on methodology of twin and family studies introductory course
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Mike Neale (director) Hermine Maes Nathan Gillespie Ben Neale Fruhling Rijsdijk Dorret Boomsma Danielle Posthuma Danielle Dick. John Hewitt (host) Jeff Lessem Stacey Cherny Nick Martin Sarah Medland Manuel Ferreira Kate Morley.

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19 th International Workshop on Methodology of Twin and Family Studies: Introductory course

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19 th international workshop on methodology of twin and family studies introductory course

Mike Neale (director)

Hermine Maes

Nathan Gillespie

Ben Neale

Fruhling Rijsdijk

Dorret Boomsma

Danielle Posthuma

Danielle Dick

John Hewitt (host)

Jeff Lessem

Stacey Cherny

Nick Martin

Sarah Medland

Manuel Ferreira

Kate Morley

19th International Workshop on Methodology of Twin and Family Studies: Introductory course


History of international methodology workshops

History of International Methodology Workshops


Attendance at international methodology workshops

Attendance at International Methodology Workshops


Causes of human variation

Causes of Human Variation

Nick Martin

Queensland Institute of Medical Research

Boulder workshop: March 6, 2006


19 th international workshop on methodology of twin and family studies introductory course

It’s all about genetic variation ...


Stature in adolescent twins

Stature in adolescent twins


19 th international workshop on methodology of twin and family studies introductory course

[Galton, 1889]


The height vs pea debate early 1900s

Biometricians

Mendelians

The height vs. pea debate(early 1900s)

Do quantitative traits have the same hereditary and evolutionary properties as discrete characters?


19 th international workshop on methodology of twin and family studies introductory course

RA Fisher (1918). Transactions of the Royal Society

of Edinburgh

52: 399-433.

var(A)=2p(1-p)a2


19 th international workshop on methodology of twin and family studies introductory course

Kenneth Mather 1911-1990

John Jinks 1929-1987


Polygenic traits

1 Gene

 3 Genotypes

 3 Phenotypes

2 Genes

 9 Genotypes

 5 Phenotypes

3 Genes

 27 Genotypes

 7 Phenotypes

4 Genes

 81 Genotypes

 9 Phenotypes

Polygenic Traits


Central limit theorem

Central Limit Theorem

The normal distribution is to be expected whenever variation is produced by the addition of a large number of effects.


19 th international workshop on methodology of twin and family studies introductory course

Multifactorial Threshold Model

of Disease

Multiple thresholds

Single threshold

unaffected affected

normal

mild

mod

severe

Diseaseliability

Disease liability


Complex trait model

Complex Trait Model

Linkage

Marker

Gene1

Linkage

disequilibrium

Mode of

inheritance

Linkage

Association

Gene2

Disease

Phenotype

Individual

environment

Gene3

Common

environment

Polygenic

background


3 stages of genetic mapping

3 Stages of Genetic Mapping

  • Are there genes influencing this trait?

    • Genetic epidemiological studies

  • Where are those genes?

    • Linkage analysis

  • What are those genes?

    • Association analysis


19 th international workshop on methodology of twin and family studies introductory course

C

D

E

A

Variance components

Additive

Genetic

Effects

Dominance

Genetic

Effects

Unique

Environment

Shared

Environment

c

a

e

d

Phenotype

P = eE + aA + cC + dD


Controversy nature vs nurture

Controversy: nature vs nurture


Designs to disentangle g e

Designs to disentangle G + E

Resemblance between relatives caused by:

  • shared Genes (G = A + D)

  • environment Common to family members (C)

    Differences between relatives caused by:

  • nonshared Genes

  • Unique environment (U or E)


19 th international workshop on methodology of twin and family studies introductory course

http://genepi.qimr.edu.au/staff/classicpapers.html


Designs to disentangle g e1

Designs to disentangle G + E

  • Family studies – G + C confounded

  • MZ twins alone – G + C confounded

  • MZ twins reared apart – rare, atypical, selective placement ?

  • Adoptions – increasingly rare, atypical, selective placement ?

  • MZ and DZ twins reared together

  • Extended twin design


19 th international workshop on methodology of twin and family studies introductory course

MZ twins reared apart - note the same way of supporting their cans of beer


19 th international workshop on methodology of twin and family studies introductory course

Body postures of MZ twins reared apart

Body postures of DZ twins reared apart


Designs to disentangle g e2

Designs to disentangle G + E

  • Family studies – G + C confounded

  • MZ twins alone – G + C confounded

  • MZ twins reared apart – rare, atypical, selective placement ?

  • Adoptions – increasingly rare, atypical, selective placement ?

  • MZ and DZ twins reared together

  • Extended twin design


Percentage of adoptees convicted of violent and property offenses by biological parents convictions

Percentage of adoptees convicted of violent and property offenses by biological parents’ convictions

  • Denmark

  • 14,427 nonfamilial adoptions 1927-47

  • Court convictions available for biological and adoptive parents

  • Mednick et al (1984) Science 224:891-4


Designs to disentangle g e3

Designs to disentangle G + E

  • Family studies – G + C confounded

  • MZ twins alone – G + C confounded

  • MZ twins reared apart – rare, atypical, selective placement ?

  • Adoptions – increasingly rare, atypical, selective placement ?

  • MZ and DZ twins reared together

  • Extended twin design


Placentation and zygosity

Placentation and zygosity

Dichorionic

Two placentas

MZ 19%

DZ 58%

Dichorionic

Fused placentas

MZ 14%

DZ 42%

Monochorionic

Diamniotic

MZ 63%

DZ 0%

Monochorionic

Monoamniotic

MZ 4%

DZ 0%


19 th international workshop on methodology of twin and family studies introductory course

Identity at marker loci - except for rare mutation

MZ and DZ twins: determining zygosity using ABI Profiler™ genotyping

(9 STR markers + sex)

MZ

DZ

DZ


19 th international workshop on methodology of twin and family studies introductory course

Total mole count for MZ and DZ twins

MZ twins - 153 pairs, r = 0.94

DZ twins - 199 pairs, r = 0.60

400

400

300

300

Twin 1

Twin 1

200

200

100

100

0

0

0

100

200

300

400

0

100

200

300

400

Twin 2

Twin 2


19 th international workshop on methodology of twin and family studies introductory course

Twin Research 6: 399-408


Genetic covariance between relatives

Genetic covariance between relatives

covG(yi,yj) = aijsA2 + dijsD2

a=additive coefficient of relationship

=2 * coefficient of kinship (= E(p))

d=coefficient of fraternity

=Prob(2 alleles are IBD)


Examples

Examples

Relativesad

Parent-offspring½0

MZ twins11

Fullsibs½ ¼

Double first cousins¼ 1/16

[Lynch & Walsh 1998]


19 th international workshop on methodology of twin and family studies introductory course

ACE Model for twin data

1

MZ=1.0 / DZ=0.5

E

C

A

A

C

E

e

c

a

a

c

e

PT1

PT2


Structural equation modeling

Both continuous and categorical variables

Systematic approach to hypothesis testing

Tests of significance

Can be extended to:

More complex questions

Multiple variables

Other relatives

Structural equation modeling


19 th international workshop on methodology of twin and family studies introductory course

E

G

VAR 1

VAR 2

VAR 3

E

E

G

G

G

E


19 th international workshop on methodology of twin and family studies introductory course

Sources of variation in male sexual orientation

EC

AC

0.30

0.70

Homosexuality

0.94

0.73

0.88

Orientation of sexual feelings

Number of same-sex partners

Attitude to sex with a man

EP

AF

AP

AA

EA

EF

< 0.01

0.04

0.08

0.16

0.11

0.06


19 th international workshop on methodology of twin and family studies introductory course

Direction of causation modeling

with cross-sectional twin data

c

D

c

Model

df

AIC

2

2

Full Bivariate

145.66 107

-69.34

Reciprocal

146.00 108 .34

-70.00

Distress

Parenting 161.74 109 16.08

-56.26

è

Parenting

Distress

146.71 109 1.05

-71.29

è

No causation

376.29 110 230.63

156.29

Final

151.26

116 5.60

-80.74

A

A

E

C

E

.20

.45

.25

.38

.55

DISTRESS

PARENTING

+

.18

.56

.63

.52

.49

.16

.67

DEP

ANX

SOM

COLD

OVERP

AUTON

C

E

A

E

A

E

C

E

A

C

E

C

E

.36

.13

.21

.11

.40

.17

.26

.21

.14

.49

.11

.37


Designs to disentangle g e4

Designs to disentangle G + E

  • Family studies – G + C confounded

  • MZ twins alone – G + C confounded

  • MZ twins reared apart – rare, atypical, selective placement ?

  • Adoptions – increasingly rare, atypical, selective placement ?

  • MZ and DZ twins reared together

  • Extended twin design


19 th international workshop on methodology of twin and family studies introductory course

Extended Twin Design

Truett, et al (1994) Behavior Genetics, 24: 35-49


19 th international workshop on methodology of twin and family studies introductory course

cm

cm

cf

mf

mm

cm

  • Extended kinship model

  • twins

  • siblings

  • parents

  • children

  • grandparents

  • aunts, uncles

  • cousins

Male- specific Additive Genes

Gender-common Additive Genes

Male- specific Additive Genes

Gender-common Additive Genes

Female Unique Environment

Male Unique Environment

0.5

0.5

0.5

ef

hmm

0.5

em

0.5

0.5

Female Twin Environment

Male Twin Environment

0.5

hfc

hmc

0.5

tf

tm

sf

Female Sibling Environment

sm

Male Sibling Environment

Female parent

Male parent

wfm

wmf

df

wmm

dm

wff

Female Dominant Genes

Male Dominant Genes

Male- specific Additive Genes

Male- specific Additive Genes

Gender-common Additive Genes

Gender-common Additive Genes

Female Unique Environment

Male Unique Environment

hmm

hfc

ef

em

hmc

rt

tm

tf

Female Twin Environment

Male Twin Environment

Female twin

Male twin

sf

sm

Female Sibling Environment

rs

Male Sibling Environment

df

dm

Male Dominant Genes

rd

Female Dominant Genes


Finding qtls

Finding QTLs

  • Linkage

  • Association


We also run a journal

We also run a journal

  • Editor: Nick Martin

  • Editorial assistant + subscriptions: Marisa Grimmer

  • Publisher: Australian Academic Press

  • Fully online

  • http://www.ists.qimr.edu.au/journal.html


Rationale for qtl analysis

Rationale for QTL analysis

  • QTL = quantitative trait locus

  • Biology: Understanding genetic variation by dissecting complex traits

    • basic biology

    • applications in agriculture

    • applications in medicine


Linkage analysis

Linkage analysis


19 th international workshop on methodology of twin and family studies introductory course

Thomas Hunt Morgan – discoverer of linkage


Linkage co segregation

Linkage = Co-segregation

A3A4

A1A2

A1A3

A2A4

A2A3

Marker allele A1

cosegregates with

dominant disease

A1A2

A1A4

A3A4

A3A2


19 th international workshop on methodology of twin and family studies introductory course

Linkage Markers…


19 th international workshop on methodology of twin and family studies introductory course

x

1/4

1/4

1/4

1/4


19 th international workshop on methodology of twin and family studies introductory course

Sib 1

Sib 2

4/16 = 1/4 sibs share BOTH parental alleles IBD = 2

8/16 = 1/2 sibs share ONE parental allele IBD = 1

4/16 = 1/4 sibs share NO parental alleles IBD = 0

IDENTITY BY DESCENT


19 th international workshop on methodology of twin and family studies introductory course

For disease traits (affected/unaffected)

Affected sib pairs selected

1000

750

500

250

IBD = 2

Expected

1

2

3

127

310

IBD = 1

Markers

IBD = 0


19 th international workshop on methodology of twin and family studies introductory course

1.00

0.75

Correlation between sibs

0.50

0.25

0.00

IBD = 0

IBD = 1

IBD = 2

For continuous measures

Unselected sib pairs


19 th international workshop on methodology of twin and family studies introductory course

rMZ = rDZ = 1

rMZ = 1, rDZ = 0.5

E

E

^

rMZ = 1, rDZ = 

C

C

e

e

A

A

c

c

a

a

Q

Q

q

q

Twin 1 mole count

Twin 2 mole count


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