Genetics and Human variation

1
Genetics and Human variation

• Nick Martin
• Queensland Institute of Medical Research
• Boulder workshop March 4, 2002

2
(No Transcript)
3

4

5
(No Transcript)
6
(No Transcript)
7
(No Transcript)
8
(No Transcript)
9
Paradigm clash ?

• Genes which cause X, rather than genes which
  cause variation in X
• not necessarily same (e.g. having a nose vs nose
  size ?) - but often so
• physiologists, experimental psychologists,
  sociobiologists vs. Quant Genet, BG, GenEpi
• see Baker BS, Taylor BJ, Hall JC (2001) Are
  complex behaviors specified by dedicated
  regulatory genes ? Cell 10513-24.

10
Individual differences

• Physical attributes (height, eye color)
• Disease susceptibility (asthma, anxiety)
• Behavior (intelligence, personality)
• Life outcomes (income, children)

11
Stature in adolescent twins
12
Continuous or Categorical ?

• Body Mass Index vs obesity
• Blood pressure vs hypertensive
• Bone Mineral Density vs fracture
• Bronchial reactivity vs asthma
• Neuroticism vs anxious/depressed
• Reading ability vs dyslexic
• Externalizing behavior vs delinquent

13
Central Limit Theorem

• The normal distribution is to be expected
  whenever variation is produced by the addition of
  a large number of effects, non-predominant
• This plausibly holds quite often

14
Polygenic Traits
15
Multifactorial Threshold Model of Disease
Multiple thresholds
Single threshold
unaffected affected
severe
mild
normal
mod
Disease liability
Disease liability
16
Genetic Epidemiology

• Establishing the role of genes and
  environment in variation in disease and complex
  traits
• Finding those genes

17
Genetically Complex Diseases

• Imprecise phenotype
• Phenocopies / sporadic cases
• Low penetrance
• Locus heterogeneity/ polygenic effects

18
Complex Trait Model
Linkage
Marker
Gene1
Linkage disequilibrium
Mode of inheritance
Linkage Association
Gene2
Disease Phenotype
Individual environment
Gene3
Common environment
Polygenic background
19
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

20
Sources of variance

• Additive genetic - A
• Interaction between alleles at same locus
  (dominance) or different loci (epistasis) D
• Common environmental influences shared by members
  of the same family C
• Non-shared environmental influences unique to the
  individual E
• Measurement error (confounded with E) unless
  replicate test-retest sample

21
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)

22
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

23
(No Transcript)
24
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

25
(No Transcript)
26
MZ concordance for human conditions

• Asthma 45
• Eczema 84
• Diabetes (type I) 56
• Schizophrenia 50
• Cleft lip/palate 30
• Club foot 23
• Homosexuality (M) 18
• Homosexuality (F) 23

27
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

28
MZ twins reared apart - note the same way of
supporting their cans of beer
29
Body postures of MZ twins reared apart
Body postures of DZ twins reared apart
30
(No Transcript)
31
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

32
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 224891-4

33
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

34
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
35
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
36
Twin studies that changed the world

• Multiple sclerosis
• Autism
• ADHD
• Schizophrenia

37
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
38

Decomposing variance
E
Covariance
A
C
0 Adoptive Siblings
0.5
1
DZ
MZ
39

Path analysis

• allows us to diagrammatically represent linear
  models for the relationships between variables
• easy to derive expectations for the variances and
  covariances of variables in terms of the
  parameters of the proposed linear model
• permits translation into matrix formulation (Mx)

40
Variance components
Additive Genetic Effects
Dominance Genetic Effects
Unique Environment
Shared Environment
c
a
e
d
Phenotype
P eE aA cC dD
41

ACE Model for twin data
1
MZ1.0 / DZ0.5
A
C
E
A
C
E
e
a
c
e
c
a
PT1
PT2
42
Fit of ACE model to mole count

• A 64, C 30, E 6
• drop A, ?21 124.0 (P lt .001)
• drop C, ?21 13.2 (P lt .001)
• therefore cant drop A or C
• and cant drop E !

43
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

44
SEM more complex questions

• Are the same genes acting in males and females ?
  (sex limitation)
• Role of age on (a) mean (b) variance (c) variance
  components
• Are G E equally important in age, country
  cohorts ? (heterogeneity)
• Are G E same in other strata (e.g.
  married/unmarried) ? ( G x E interaction)

45
(No Transcript)
46
Sources of variation in male sexual orientation
EC
AC
0.30
0.70
Homosexuality
0.94
0.73
0.88
Number of same-sex partners
Orientation of sexual feelings
Attitude to sex with a man
EP
AP
AF
AA
EA
EF
lt 0.01
0.08
0.04
0.16
0.06
0.11
47
Direction of causation modeling with
cross-sectional twin data
48
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

49
?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
0.5
ef
hmm
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
Gender-common Additive Genes
Male- specific Additive Genes
Male- specific Additive Genes
Gender-common Additive Genes
Female Unique Environment
Male Unique Environment
hmm
ef
hfc
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
Female Dominant Genes
rd
50
3 Stages of Genetic Mapping

• Are there genes influencing this trait?
• Epidemiological studies
• Where are those genes?
• Linkage analysis
• What are those genes?
• Association analysis

51
Linkage analysis
52
Linkage Co-segregation

A3A4
A1A2
A2A4
A1A3
A2A3
Marker allele A1 cosegregates with dominant
disease
A1A2
A1A4
A3A4
A3A2
53
Linkage Analysis

• Sharing between relatives
• Identifies large regions
• Include several candidates
• Complex disease
• Scans on sets of small families popular
• No strong assumptions about disease alleles
• Low power
• Limited resolution

54
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
55
Flat mole count - genome scan in 274 twin families
56
3 Stages of Genetic Mapping

• Are there genes influencing this trait?
• Epidemiological studies
• Where are those genes?
• Linkage analysis
• What are those genes?
• Association analysis

57
(No Transcript)
58
Association Analysis

• Sharing between unrelated individuals
• Trait alleles originate in common ancestor
• High resolution
• Recombination since common ancestor
• Large number of independent tests
• Powerful if assumptions are met
• Same disease haplotype shared by many patients
• Sensitive to population structure

59
(No Transcript)
60
(No Transcript)
61
First (unequivocal) positional cloning of a
complex disease QTL !
62
but can we find the God gene?

• Time will tell.