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1. Principles of Genetic
Epidemiology
Kirsten Ohm Kyvik

2. 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)

3. 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

4. Fundamentals
 Definition of phenotype
 Classification of phenotype
 Natural history of phenotype

5. 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

6. Multifactorial inheritance
Monogenic Quantitativ
Mød en forsker

7. T
R
E
S
H
O
L
D
M
O
D
E
L

8. Family studies

9. 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

10. Familial aggregation = genetic aetiology?
Against:
 Effect of:

11. 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

12. Expected risk pattern
0
10
20
30
40
50
60
70
MZ twins 1-degr 2-degr 3-degr
Risiko
%
Family risk

13. Parkinson’s disease in Iceland
(Sveinbjørnsdottir et al. NEJM, 2000)
Relatives Risk ratio
(family vs
population)
p
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

14. 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%

15. Smoothed prevalence
0
1
2
3
4
5
6
7
1950 1960 1970 1980 1990 2000
Year
All Boys
Girls

16. Recurrence risk in relatives
Recurrence risk % (95% Confidence Interval)
Group Female Male All
Population 0.11 (0.06-
0.15)
0.43 (0.40-
0.46)
0.27 (0.24-
0.30)
1.degree 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 (0.14-
5.3)
4.5 (0.10-
8.3)
4.5 (0.24-
8.3)
Siblings 11.4 (4.0-
17.5)
5.1 (3.0-
10.8)
6.6 (4.7-9.8)
2. degree
Grandpa
rents
0.76 (-0.13-
1.5)
0.51 (0.10-
1.1)
0.57 (0.20-
1.0)

17. Twin studies

19. 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

20. DESIGNS
 Classical twin study
 Classical twin study with separated
MZ twins
 Twin family studies
 Twin-control studies

21. Classical twin study
MZ pairs:
DZ pairs:

22. DESIGNS
 Classical twin study
 Classical twin study with separated
MZ twins
 Twin family studies
 Twin-control studies

23. Is a phenotype genetically determined?
• Categorical data
• Continous data

24. 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:

25. Probandwise concordance
Estimate of the casewise probability by the
proband method.
2C1 + C2
2C1 + C2 + D
-----------------

26. Concordance
CMZ = CDZ
CMZ > CDZ
CMZ <1.0 (100%)

27. Solutions to problems with age at diagnosis
 Survival analysis
Actuarial/Kaplan Meier methodology
Frailty models
Newer models
 Others?
Correction methods

28. Concordance type 1 diabetes
Zygosity Pairs Concordance
(probands) Pairwise* Probandwise Cumulated
Conc Disc
MZ 10(18) 16 0.38 0.53 0.70
[0.20-0.59] [0.33-0.73] [0.45-0.95)
DZ 4 (8) 65 0.06 0.11 0.13
[0.02-0.14] [0.05-0.21] [0.04-0.21]
( ) Number of probands; [ ] 95% confidence limits.
* Chi2
1d.f. = 10.93, p < 0.001

29. Cumulative concordance type 1 diabetes
Interpretable as cumulative risk from
birth
%
0-100
Age
0-40
MZ
0.70
DZ
0.13

30. Correlations
Twin-twin correlations
rMZ = rDZ
rMZ > rDZ
rMZ < 1.0 (100%)

31. lnTSH
in
Twin
2
lnTSH in Twin 1
-2 -1 0 1 2
-2
-1
0
1
2
lnTSH
in
Twin
2
lnTSH in Twin 1
-2 -1 0 1 2
-2
-1
0
1
2
rMZ=0.64 (CI 0.56-0.70) rDZ=0.29 (CI 0.18-0.39)
MZ n=284 pairs DZ n=285 pairs
p<0.00005
INTRACLASS CORRELATIONS
lnTSH (Pia Skov Hansen)

32. 0,6625 0,6358
0,2915
0,1814
0,3577
0,6373
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
All Male Female
rMZ
rDZ
INTRACLASS CORRELATIONS
lnTSH

33. Aetiological components
 Additive genetic variance
 Dominant genetic variance/epistasis
 Common environmental variance
 Unique environmental variance

34. Genotype Group
Model AA Aa aa
A is
Dominant
A is
Recessive
A is
Co-Dominant
Inheritance Models in Single Gene Trait

35. Population Mean
Model -x 0 +x
A is Completely
Dominant
aa
AA
Aa
A is Partially
Dominant
aa Aa AA
A is Not
Dominant
aa Aa AA
Inheritance Models in Quantitative Trait

36. Heritability
 V (total) = VG + VE
 V (total) = VA + VD + VI + VC + VE
 h2
narrow = VA/VA + VD + VI + VC + VE
 h2
broad = VA + VD + VI/VA + VD + VI + VC + VE

37. 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

38. Correlations and aetiological models
rMZ < 1
rMZ = rDZ = 0
rMZ = rDZ > 0
rMZ = 2rDZ > 0
rMZ > 2rDZ
rMZ < 2rDZ

39. Aetiological models and genetic variation
 Variance analysis
 Regression analysis
 Structural equation modelling

40. Path model for twin analysis

41. Pleiotrophy

42. Unique
Environmental
effect
0.36
Genetic
effect
0.64
The genetic effects account for 64% of the variation
RESULTS TSH-LEVEL

43. BMI Waist
Gluc12
0
Ins0 SBP DBP HDL TG
BMI
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)
Waist
0.85
(0.01)
-0.16
(0.06)
0.51
(0.05)
0.30
(0.05)
0.26
(0.05)
-0.19
(0.06)
0.26
(0.06)
Gluc12
0
0.02
(0.03)
0.03
(0.03)
0.09
(0.08)
0.12
(0.07)
0.11
(0.07)
-0.02
(0.08)
0.23
(0.08)
Ins0
0.46
(0.02)
0.46
(0.02)
0.13
(0.03)
0.31
(0.06)
0.29
(0.06)
-0.17
(0.07)
0.31
(0.07)
SBP
0.28
(0.03)
0.26
(0.03)
0.14
(0.03)
0.23
(0.03)
0.71
(0.03)
-0.09
(0.06)
0.28
(0.06)
DBP
0.26
(0.03)
0.23
(0.03)
0.13
(0.03)
0.23
(0.03)
0.69
(0.02)
-0.01
(0.06)
0.27
(0.06)
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)
-0.24
(0.07)
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)
-0.22
(0.03)
Multivariate ACE Model

44. Important assumptions
• Biology of twinning
• ”True” zygosity
• Equal environment assumption
• true or not true?
• Generalisability

45. Adoption studies

46. Adoption design
Adoptees are expected to

47. 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

48. Assumptions and problems
 Early adoption
 Non-familial adoption
 Comparable environment in biological and adoptive
family
 Contact to biological family
 Intra-uterine environment
 Transcultural adoptions

49. 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

50. Comparison heritability
Heritability
Twin studies
MZA
50-90%
60-70%
Family studies 20-80%
Adoption studies 20-60%