Principles of Genetic
Epidemiology
Kirsten Ohm Kyvik
Genetic epidemiology
Genetic epidemiology deals with the etiology,
distribution, and control of disease
(epidemiology) in groups of relatives and with
inherited causes of disease (genetics) in
populations (adapted from Morton and Chung
1978)
Steps in genetic epidemiology
•
•
•

Evidence for familial aggregation
Is familial aggregation due to genes or environment?
Specific genetic mechanisms
Taking advantage of designs involving
 Families
 Twins
 Adoptees and their families
Fundamentals
 Definition of phenotype
 Classification of phenotype
 Natural history of phenotype
Adaptation of concept of causation
 Family status changes risk profile
 Observations on family members not independent
 Boundary between cohort and case-control studies is
blurred
Multifactorial inheritance
Monogenic
Mød en forsker
Quantitativ
T
R
E
S
H
O
L
D
M
O
D
E
L
Family studies
Design of familiestudies

Identify probands – ”ascertainment probability”

Information on phenotype in relatives (1.degree, 2.
degree etc.)

Compare groups of relatives

Compare with background population
Familial aggregation = genetic aetiology?
Against:
 Effect of:
Groups of relatives
Risk of siblings compared to risk in parent-offspring
• RR(sib) = RR(par)
• RR(sib) >> RR(par
• RR(sib) and RR(par) small, but bigger than
population risk
Expected risk pattern
70
60
Risiko %
50
40
Family risk
30
20
10
0
MZ twins
1-degr
2-degr
3-degr
Parkinson’s disease in Iceland
(Sveinbjørnsdottir et al. NEJM, 2000)
Relatives
Risk ratio
p
(family vs
population)
Sibling
6.3
<0.001
Children
3.0
0.001
Nephew/niece
2.4
<0.001
Cousin
2.4
0.1
Spouse
1.9
0.16
Genetic epidemiology of
infantile hypertrophic pyloric stenosis
The IHPS register
•
•
•
•
•
Funen based
Cases from 1950 to 2004
A total of 892 cases, 870 identified in CPR
Questionnaire send to all cases
Reply from 65%
Smoothed prevalence
7
6
5
4
3
2
1
0
1950
1960
1970
1980
Year
All
Girls
1990
Boys
2000
Recurrence risk in relatives
Recurrence risk % (95% Confidence Interval)
Group
Female
Population
1.degree
0.11
Male
(0.060.15)
0.43
All
(0.400.46)
0.27
(0.240.30)
5.7
(3.9-9.5)
4.4
(3.4-6.1)
4.8
(4.1-7.0)
Parent
4.5
(1.4-7.4)
3.9
(2.4-5.7)
4.0
(2.9-6.2)
Offspring
4.5
(0.145.3)
4.5
(0.108.3)
4.5
(0.248.3)
11.4
(4.017.5)
5.1
(3.010.8)
6.6
(4.7-9.8)
Siblings
2. degree
Grandpa
rents
0.76
(-0.131.5)
0.51
(0.101.1)
0.57
(0.201.0)
Twin studies
Aims
•
•
•
•
•
•
What is the risk/recurrence risk in twins
Is a phenotype genetically determined
Aetiological models
Size of genetic variation / heritability
Genes, markers, chromosomal regions
Environmental determinants
DESIGNS
 Classical
twin study
 Classical
twin study with separated
MZ twins
 Twin
family studies
 Twin-control
studies
Classical twin study
MZ pairs:
DZ pairs:
DESIGNS
 Classical
twin study
 Classical
twin study with separated
MZ twins
 Twin
family studies
 Twin-control
studies
Is a phenotype genetically determined?
• Categorical data
• Continous data
Types of concordance
Pairwise: Probability that both in a pair is
affected:
Casewise/probandwise: Probability that a twin
is diseased given that the twin partner is
diseased:
Probandwise concordance
Estimate of the casewise probability by the
proband method.
2C1 + C2
-----------------
2C1 + C2 + D
Concordance
CMZ = CDZ
CMZ > CDZ
CMZ <1.0 (100%)
Solutions to problems with age at diagnosis

Survival analysis
Actuarial/Kaplan Meier methodology
Frailty models
Newer models

Others?
Correction methods
Concordance type 1 diabetes
Zygosity
Pairs
(probands)
Conc
Disc
Concordance
Pairwise* Probandwise
MZ
10(18)
16
0.38
[0.20-0.59]
0.53
[0.33-0.73]
0.70
[0.45-0.95)
DZ
4 (8)
65
0.06
[0.02-0.14]
0.11
[0.05-0.21]
0.13
[0.04-0.21]
( ) Number of probands; [ ] 95% confidence limits.
* Chi21d.f. = 10.93, p < 0.001
Cumulated
Cumulative concordance type 1 diabetes
Interpretable as cumulative risk from
birth
%
0-100
MZ
0.70
DZ
0.13
Age
0-40
Correlations
Twin-twin correlations
rMZ = rDZ
rMZ > rDZ
rMZ < 1.0 (100%)
INTRACLASS CORRELATIONS
lnTSH (Pia Skov Hansen)
MZ n=284 pairs
2
DZ n=285 pairs
rMZ=0.64 (CI 0.56-0.70)
2
1
ln T S H in T win 2
1
ln T S H in T win 2
rDZ=0.29 (CI 0.18-0.39)
0
0
-1
-1
-2
-2
-2
-1
0
lnTSH in Twin 1
1
2
p<0.00005
-2
-1
0
lnTSH in Twin 1
1
2
INTRACLASS CORRELATIONS
lnTSH
1
0,9
0,8
0,7
0,6
rMZ
0,5
rDZ
0,4
0,3
0,6625
0,6373
0,6358
0,2
0,3577
0,2915
0,1
0,1814
0
All
Male
Female
Aetiological components
 Additive genetic variance
 Dominant genetic variance/epistasis
 Common environmental variance
 Unique environmental variance
Inheritance Models in Single Gene Trait
Genotype Group
Model
A is
Dominant
A is
Recessive
A is
Co-Dominant
AA
Aa
aa
Inheritance Models in Quantitative Trait
Model
-x
A is Completely
Dominant
aa
A is Partially
Dominant
aa
A is Not
Dominant
aa
Population Mean
0
+x
AA
Aa
Aa
Aa
AA
AA
Heritability




V (total) = VG + VE
V (total) = VA + VD + VI + VC + VE
h2narrow = VA/VA + VD + VI + VC + VE
h2broad = VA + VD + VI/VA + VD + VI + VC + VE
Heritability
 Function of population, NOT a constant
 Does not apply to individuals
 Biased if mean and variance not the same in MZ
and DZ
 Greater MZ covariance will inflate h2
Correlations and aetiological models
rMZ < 1
rMZ = rDZ = 0
rMZ = rDZ > 0
rMZ = 2rDZ > 0
rMZ > 2rDZ
rMZ < 2rDZ
Aetiological models and genetic variation
 Variance analysis
 Regression analysis
 Structural equation modelling
Path model for twin analysis
Pleiotrophy
RESULTS TSH-LEVEL
Unique
Environmental
effect
0.36
Genetic
effect
0.64
The genetic effects account for 64% of the variation
Multivariate ACE Model
BMI
BMI
Waist
Gluc12
0
Ins0
SBP
DBP
HDL
TG
0.86
(0.01)
-0.13
(0.06)
0.48
(0.04)
0.29
(0.04)
0.27
(0.04)
-0.18
(0.05)
0.20
(0.06)
-0.16
(0.06)
0.51
(0.05)
0.30
(0.05)
0.26
(0.05)
-0.19
(0.06)
0.26
(0.06)
0.09
(0.08)
0.12
(0.07)
0.11
(0.07)
-0.02
(0.08)
0.23
(0.08)
0.31
(0.06)
0.29
(0.06)
-0.17
(0.07)
0.31
(0.07)
0.71
(0.03)
-0.09
(0.06)
0.28
(0.06)
-0.01
(0.06)
0.27
(0.06)
Waist
0.85
(0.01)
Gluc12
0
0.02
0.03
(0.03) (0.03)
0.46
Ins0
0.46
(0.02)
SBP
0.28
(0.03)
0.26
(0.03)
0.14
(0.03)
0.23
(0.03)
DBP
0.26
(0.03)
0.23
(0.03)
0.13
(0.03)
0.23
(0.03)
0.69
(0.02)
HDL
-0.17
(0.03)
-0.19
(0.03)
-0.04
(0.03)
-0.14
(0.03)
-0.01
(0.03)
-0.03
(0.03)
TG
0.22
(0.03)
0.27
(0.03)
0.20
(0.03)
0.35
(0.02)
0.20
(0.03)
0.20
(0.03)
(0.02)
0.13
(0.03)
-0.24
(0.07)
-0.22
(0.03)
Important assumptions
• Biology of twinning
• ”True” zygosity
• Equal environment assumption
•
true or not true?
• Generalisability
Adoption studies
Adoption design
Adoptees are expected to
Early death in adoptees
Cause of death
Parent dead < 50 yrs
Parent dead < 70 yrs
Natural
Bio
Ado
1.98*
0.96
1.49
0.8
Infection
Bio
Ado
5.81*
0.73
5*
1
Vasculær
Bio
Ado
4.52*
3.02
1.92
1.5
Cancer
Bio
Ado
1.19
5.16*
0.87
1.49
Assumptions and problems
 Early adoption
 Non-familial adoption
 Comparable environment in biological and adoptive
family
 Contact to biological family
 Intra-uterine environment
 Transcultural adoptions
Comparison of correlations
Correlation
Twin studies
MZ
DZ
MZA
0.7
0.36
0.7
Family studies
PO
Sib
0.27
0.25
Adoption studies
Bio
Ado
0.17
0.1
Comparison heritability
Heritability
Twin studies
MZA
50-90%
60-70%
Family studies
20-80%
Adoption studies
20-60%